BIN1

UniProt ID: O00499
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

BIN1 encodes amphiphysin II, a BAR/N-BAR and SH3-domain membrane-remodeling adaptor with extensive alternative splicing in brain and skeletal muscle. BIN1 binds phospholipid membranes, senses and generates membrane curvature, promotes lipid tubulation, and organizes membrane domains used in endocytosis, synaptic-vesicle cycling, endosomal sorting, and skeletal-muscle T-tubule formation. Through SH3-domain interactions with endocytic proteins such as dynamin and clathrin/AP2-associated machinery, BIN1 links curved membranes to vesicle trafficking and cytoskeletal organization. Additional context-specific functions include nuclear/MYC-related tumor-suppressor activities, tau and clusterin interactions, and regulation of BACE1 trafficking and amyloid-beta production.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005886 plasma membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0008021 synaptic vesicle
IBA
GO_REF:0000033 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0005543 phospholipid binding
IBA
GO_REF:0000033 		ACCEPT
Summary: BIN1 BAR/N-BAR domains bind phospholipid membranes and generate or sense membrane curvature.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0048156 tau protein binding
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: BIN1-tau interaction is experimentally supported and Alzheimer-relevant, but it is a context-specific disease/pathology interaction rather than the primary BAR-domain membrane-remodeling role.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0005634 nucleus
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not the main BIN1 membrane-remodeling function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0005737 cytoplasm
IEA
GO_REF:0000120 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005768 endosome
IEA
GO_REF:0000044 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0006897 endocytosis
IEA
GO_REF:0000117 		ACCEPT
Summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related interactions and membrane remodeling.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0016020 membrane
IEA
GO_REF:0000117 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0030100 regulation of endocytosis
IEA
GO_REF:0000002 		ACCEPT
Summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related interactions and membrane remodeling.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0030315 T-tubule
IEA
GO_REF:0000120 		ACCEPT
Summary: BIN1 is required for muscle membrane organization, especially T-tubule formation and associated sarcomeric membrane domains.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0030424 axon
IEA
GO_REF:0000117 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0051649 establishment of localization in cell
IEA
GO_REF:0000117 		MARK AS OVER ANNOTATED
Summary: This process is too broad for BIN1 compared with specific endocytosis, vesicle sorting, and membrane-remodeling terms.
Reason: Use more informative trafficking/endocytosis and membrane-remodeling terms instead of broad establishment of localization in cell.
GO:0005515 protein binding
IPI
PMID:10903846
Bin2, a functionally nonredundant member of the BAR adaptor ... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:12604805
Identification and characterization of amphiphysin II as a n... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:12668730
Sorting nexin 4 and amphiphysin 2, a new partnership between... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:16275660
Identification of VCP/p97, carboxyl terminus of Hsp70-intera... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:16530520
The SH3 binding motif of HCV [corrected] NS5A protein intera... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:18647389
The central proline rich region of POB1/REPS2 plays a regula... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:18985028
Hepatitis C virus infection protein network. 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:23917616
The myotubularin-amphiphysin 2 complex in membrane tubulatio... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:24169621
Elucidating novel hepatitis C virus-host interactions using ... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:31413325
HENA, heterogeneous network-based data set for Alzheimer's d... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:32552912
Upregulation of RIN3 induces endosomal dysfunction in Alzhei... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human ce... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0042802 identical protein binding
IPI
PMID:23917616
The myotubularin-amphiphysin 2 complex in membrane tubulatio... 		KEEP AS NON CORE
Summary: This annotation is plausible or supported, but it is more context-specific or less informative than the core BIN1 membrane-remodeling/endocytic functions.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0042802 identical protein binding
IPI
PMID:31413325
HENA, heterogeneous network-based data set for Alzheimer's d... 		KEEP AS NON CORE
Summary: This annotation is plausible or supported, but it is more context-specific or less informative than the core BIN1 membrane-remodeling/endocytic functions.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0008021 synaptic vesicle
IEA
GO_REF:0000107 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0030018 Z disc
IEA
GO_REF:0000107 		ACCEPT
Summary: BIN1 is required for muscle membrane organization, especially T-tubule formation and associated sarcomeric membrane domains.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0031674 I band
IEA
GO_REF:0000107 		ACCEPT
Summary: BIN1 is required for muscle membrane organization, especially T-tubule formation and associated sarcomeric membrane domains.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0033268 node of Ranvier
IEA
GO_REF:0000107 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0043194 axon initial segment
IEA
GO_REF:0000107 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0043196 varicosity
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: This annotation is plausible or supported, but it is more context-specific or less informative than the core BIN1 membrane-remodeling/endocytic functions.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0043679 axon terminus
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: This annotation is plausible or supported, but it is more context-specific or less informative than the core BIN1 membrane-remodeling/endocytic functions.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0044300 cerebellar mossy fiber
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: This annotation is plausible or supported, but it is more context-specific or less informative than the core BIN1 membrane-remodeling/endocytic functions.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0044877 protein-containing complex binding
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: This annotation is plausible or supported, but it is more context-specific or less informative than the core BIN1 membrane-remodeling/endocytic functions.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0045807 positive regulation of endocytosis
IEA
GO_REF:0000107 		ACCEPT
Summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related interactions and membrane remodeling.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0048488 synaptic vesicle endocytosis
IEA
GO_REF:0000107 		ACCEPT
Summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related interactions and membrane remodeling.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0051020 GTPase binding
IEA
GO_REF:0000107 		ACCEPT
Summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related interactions and membrane remodeling.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0098850 extrinsic component of synaptic vesicle membrane
IEA
GO_REF:0000107 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0098978 glutamatergic synapse
IEA
GO_REF:0000107 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0000122 negative regulation of transcription by RNA polymerase II
IDA
PMID:10412034
Induction of apoptosis and differentiation in neuroblastoma ... 		KEEP AS NON CORE
Summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not the main BIN1 membrane-remodeling function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0005634 nucleus
IDA
PMID:8782822
BIN1 is a novel MYC-interacting protein with features of a t... 		KEEP AS NON CORE
Summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not the main BIN1 membrane-remodeling function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0010564 regulation of cell cycle process
IDA
PMID:8782822
BIN1 is a novel MYC-interacting protein with features of a t... 		KEEP AS NON CORE
Summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not the main BIN1 membrane-remodeling function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0090571 RNA polymerase II transcription repressor complex
IPI
PMID:15992821
A structure-based model of the c-Myc/Bin1 protein interactio... 		KEEP AS NON CORE
Summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not the main BIN1 membrane-remodeling function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0005737 cytoplasm
EXP
PMID:9182667
Amphiphysin II (SH3P9; BIN1), a member of the amphiphysin/Rv... 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005768 endosome
ISS
GO_REF:0000024 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0008289 lipid binding
EXP
PMID:18658220
Structure and dynamics of helix-0 of the N-BAR domain in lip... 		ACCEPT
Summary: BIN1 BAR/N-BAR domains bind phospholipid membranes and generate or sense membrane curvature.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0060988 lipid tube assembly
IDA
PMID:18658220
Structure and dynamics of helix-0 of the N-BAR domain in lip... 		ACCEPT
Summary: BIN1 has intrinsic membrane-tubulating activity and supports lipid tube or membrane tubule formation.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:1901380 negative regulation of potassium ion transmembrane transport
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: This annotation is plausible or supported, but it is more context-specific or less informative than the core BIN1 membrane-remodeling/endocytic functions.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:1903946 negative regulation of ventricular cardiac muscle cell action potential
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: This annotation is plausible or supported, but it is more context-specific or less informative than the core BIN1 membrane-remodeling/endocytic functions.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0030838 positive regulation of actin filament polymerization
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: This annotation is plausible or supported, but it is more context-specific or less informative than the core BIN1 membrane-remodeling/endocytic functions.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0086091 regulation of heart rate by cardiac conduction
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: This annotation is plausible or supported, but it is more context-specific or less informative than the core BIN1 membrane-remodeling/endocytic functions.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:1904878 negative regulation of calcium ion transmembrane transport via high voltage-gated calcium channel
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: This annotation is plausible or supported, but it is more context-specific or less informative than the core BIN1 membrane-remodeling/endocytic functions.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0030424 axon
ISS
PMID:32552912
Upregulation of RIN3 induces endosomal dysfunction in Alzhei... 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0030425 dendrite
ISS
PMID:32552912
Upregulation of RIN3 induces endosomal dysfunction in Alzhei... 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0031982 vesicle
ISS
PMID:32552912
Upregulation of RIN3 induces endosomal dysfunction in Alzhei... 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0019828 aspartic-type endopeptidase inhibitor activity
IMP
PMID:27179792
BIN1 regulates BACE1 intracellular trafficking and amyloid-β... 		MODIFY
Summary: BIN1 regulates BACE1 abundance and amyloid-beta production by endosomal trafficking and lysosomal degradation, not by acting as a direct aspartic protease inhibitor.
Reason: Replace direct aspartic-type endopeptidase inhibitor activity with protease binding plus BACE1 trafficking/amyloid-output process terms.
GO:1902430 negative regulation of amyloid-beta formation
IMP
PMID:27179792
BIN1 regulates BACE1 intracellular trafficking and amyloid-β... 		KEEP AS NON CORE
Summary: BIN1 regulation of BACE1 trafficking and amyloid-beta production is supported, but is a cargo-specific Alzheimer-relevant context rather than the core BIN1 function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0008333 endosome to lysosome transport
IMP
PMID:27179792
BIN1 regulates BACE1 intracellular trafficking and amyloid-β... 		KEEP AS NON CORE
Summary: BIN1 regulation of BACE1 trafficking and amyloid-beta production is supported, but is a cargo-specific Alzheimer-relevant context rather than the core BIN1 function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0048156 tau protein binding
NAS
PMID:28386764
Roles of tau protein in health and disease. 		KEEP AS NON CORE
Summary: BIN1-tau interaction is experimentally supported and Alzheimer-relevant, but it is a context-specific disease/pathology interaction rather than the primary BAR-domain membrane-remodeling role.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0005515 protein binding
IPI
PMID:17676042
Mutations in amphiphysin 2 (BIN1) disrupt interaction with d... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0033292 T-tubule organization
IDA
PMID:24755653
Mutations in BIN1 associated with centronuclear myopathy dis... 		ACCEPT
Summary: BIN1 is required for muscle membrane organization, especially T-tubule formation and associated sarcomeric membrane domains.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0030315 T-tubule
ISS
GO_REF:0000024 		ACCEPT
Summary: BIN1 is required for muscle membrane organization, especially T-tubule formation and associated sarcomeric membrane domains.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0033292 T-tubule organization
ISS
GO_REF:0000024 		ACCEPT
Summary: BIN1 is required for muscle membrane organization, especially T-tubule formation and associated sarcomeric membrane domains.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0002020 protease binding
IPI
PMID:27179792
BIN1 regulates BACE1 intracellular trafficking and amyloid-β... 		KEEP AS NON CORE
Summary: BIN1 regulation of BACE1 trafficking and amyloid-beta production is supported, but is a cargo-specific Alzheimer-relevant context rather than the core BIN1 function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0005634 nucleus
IDA
PMID:25051234
Intracellular clusterin interacts with brain isoforms of the... 		KEEP AS NON CORE
Summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not the main BIN1 membrane-remodeling function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0005737 cytoplasm
IDA
PMID:25051234
Intracellular clusterin interacts with brain isoforms of the... 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005856 cytoskeleton
IDA
PMID:25051234
Intracellular clusterin interacts with brain isoforms of the... 		ACCEPT
Summary: BIN1 couples membrane remodeling to the actin/cytoskeletal system, including direct actin filament binding/remodeling evidence.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0006897 endocytosis
TAS
PMID:23399914
Increased expression of BIN1 mediates Alzheimer genetic risk... 		ACCEPT
Summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related interactions and membrane remodeling.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0006897 endocytosis
TAS
PMID:25051234
Intracellular clusterin interacts with brain isoforms of the... 		ACCEPT
Summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related interactions and membrane remodeling.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0007010 cytoskeleton organization
TAS
PMID:23399914
Increased expression of BIN1 mediates Alzheimer genetic risk... 		ACCEPT
Summary: BIN1 couples membrane remodeling to the actin/cytoskeletal system, including direct actin filament binding/remodeling evidence.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0016020 membrane
IDA
PMID:25051234
Intracellular clusterin interacts with brain isoforms of the... 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0016020 membrane
TAS
PMID:28755476
Regulation of the interaction between the neuronal BIN1 isof... 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0030276 clathrin binding
TAS
PMID:25051234
Intracellular clusterin interacts with brain isoforms of the... 		ACCEPT
Summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related interactions and membrane remodeling.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0048156 tau protein binding
IPI
PMID:25051234
Intracellular clusterin interacts with brain isoforms of the... 		KEEP AS NON CORE
Summary: BIN1-tau interaction is experimentally supported and Alzheimer-relevant, but it is a context-specific disease/pathology interaction rather than the primary BAR-domain membrane-remodeling role.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0051087 protein-folding chaperone binding
IPI
PMID:25051234
Intracellular clusterin interacts with brain isoforms of the... 		KEEP AS NON CORE
Summary: This annotation is plausible or supported, but it is more context-specific or less informative than the core BIN1 membrane-remodeling/endocytic functions.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8867754 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868230 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868236 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868648 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868651 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868658 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868659 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868660 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868661 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8869438 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8871193 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8871194 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0005515 protein binding
IPI
PMID:26506308
Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by ... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0006997 nucleus organization
IMP
PMID:26506308
Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by ... 		KEEP AS NON CORE
Summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not the main BIN1 membrane-remodeling function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0051015 actin filament binding
IDA
PMID:26506308
Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by ... 		ACCEPT
Summary: BIN1 couples membrane remodeling to the actin/cytoskeletal system, including direct actin filament binding/remodeling evidence.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0016020 membrane
IDA
PMID:16530520
The SH3 binding motif of HCV [corrected] NS5A protein intera... 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0043065 positive regulation of apoptotic process
IDA
PMID:16530520
The SH3 binding motif of HCV [corrected] NS5A protein intera... 		KEEP AS NON CORE
Summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not the main BIN1 membrane-remodeling function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0070063 RNA polymerase binding
IPI
PMID:16530520
The SH3 binding motif of HCV [corrected] NS5A protein intera... 		KEEP AS NON CORE
Summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not the main BIN1 membrane-remodeling function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0030018 Z disc
ISS
GO_REF:0000024 		ACCEPT
Summary: BIN1 is required for muscle membrane organization, especially T-tubule formation and associated sarcomeric membrane domains.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0031674 I band
ISS
GO_REF:0000024 		ACCEPT
Summary: BIN1 is required for muscle membrane organization, especially T-tubule formation and associated sarcomeric membrane domains.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0033268 node of Ranvier
ISS
GO_REF:0000024 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0043194 axon initial segment
ISS
GO_REF:0000024 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0043065 positive regulation of apoptotic process
IMP
PMID:10412034
Induction of apoptosis and differentiation in neuroblastoma ... 		KEEP AS NON CORE
Summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not the main BIN1 membrane-remodeling function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0048711 positive regulation of astrocyte differentiation
IMP
PMID:10412034
Induction of apoptosis and differentiation in neuroblastoma ... 		KEEP AS NON CORE
Summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not the main BIN1 membrane-remodeling function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0005515 protein binding
IPI
PMID:19004523
The membrane-tubulating potential of amphiphysin 2/BIN1 is d... 		MARK AS OVER ANNOTATED
Summary: The interaction may be real, but generic protein binding is not an informative molecular-function annotation for BIN1.
Reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
GO:0060987 lipid tube
IMP
PMID:19004523
The membrane-tubulating potential of amphiphysin 2/BIN1 is d... 		ACCEPT
Summary: BIN1 has intrinsic membrane-tubulating activity and supports lipid tube or membrane tubule formation.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0060988 lipid tube assembly
IMP
PMID:19004523
The membrane-tubulating potential of amphiphysin 2/BIN1 is d... 		ACCEPT
Summary: BIN1 has intrinsic membrane-tubulating activity and supports lipid tube or membrane tubule formation.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0030424 axon
IDA
PMID:23399914
Increased expression of BIN1 mediates Alzheimer genetic risk... 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.
GO:0045664 regulation of neuron differentiation
IMP
PMID:10412034
Induction of apoptosis and differentiation in neuroblastoma ... 		KEEP AS NON CORE
Summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not the main BIN1 membrane-remodeling function.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0048156 tau protein binding
IPI
PMID:23399914
Increased expression of BIN1 mediates Alzheimer genetic risk... 		KEEP AS NON CORE
Summary: BIN1-tau interaction is experimentally supported and Alzheimer-relevant, but it is a context-specific disease/pathology interaction rather than the primary BAR-domain membrane-remodeling role.
Reason: Retain as non-core because the annotation is supported or plausible but represents a context-specific cargo, disease, nuclear/tumor-suppressor, or downstream phenotype rather than BIN1 primary membrane-remodeling function.
GO:0005737 cytoplasm
IDA
GO_REF:0000054 		ACCEPT
Summary: This location or process is consistent with BIN1 membrane-remodeling and endocytic adaptor function in neuronal and muscle contexts.
Reason: This location is consistent with BIN1 isoform-specific function at cytosolic membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and skeletal-muscle T-tubules.
GO:0015629 actin cytoskeleton
TAS
PMID:9182667
Amphiphysin II (SH3P9; BIN1), a member of the amphiphysin/Rv... 		ACCEPT
Summary: BIN1 couples membrane remodeling to the actin/cytoskeletal system, including direct actin filament binding/remodeling evidence.
Reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule organization.

Core Functions

BIN1 uses its N-BAR/BAR domain to bind phospholipid membranes, sense and generate membrane curvature, and drive membrane tubulation. This membrane-remodeling activity underlies T-tubule formation in skeletal muscle and curved membrane intermediates in endocytosis and endosomal trafficking.

Molecular Function:
phospholipid binding
Directly Involved In:
lipid tube assembly T-tubule organization endocytosis regulation of endocytosis cytoskeleton organization
Cellular Locations:
plasma membrane T-tubule endosome membrane cytosol
Supporting Evidence:
  • PMID:18658220
    BAR domains generate and sense membrane curvature
  • PMID:18658220
    Deletion of helix-0 reduced tubulation of liposomes by the BAR domain
  • PMID:24755653
    two mutants showed impaired membrane tubulation both in vivo and in vitro
  • PMID:24755653
    BIN1, which contains an N-BAR domain, is assumed to be essential for biogenesis of plasma membrane invaginations (T-tubules) in muscle tissues
  • PMID:19004523
    Amphiphysin 2/BIN1 may be an anchoring point on membranes for CLIP-170
  • file:human/BIN1/BIN1-deep-research-falcon.md
    The BAR domain constitutes the primary determinant of this membrane-sculpting capacity, engaging membranes through electrostatic interactions and mechanically deforming lipid bilayers into highly curved tubular and vesicular structures

BIN1 acts as an endocytic adaptor through SH3-domain and isoform-specific interactions with dynamin and clathrin/AP2-associated machinery, linking curved membrane domains to synaptic-vesicle cycling, endocytosis, and membrane trafficking.

Molecular Function:
GTPase binding
Directly Involved In:
synaptic vesicle endocytosis endocytosis positive regulation of endocytosis T-tubule organization
Cellular Locations:
synaptic vesicle extrinsic component of synaptic vesicle membrane axon initial segment node of Ranvier axon
Supporting Evidence:
  • PMID:17676042
    the functional interaction between BIN1 and DNM2 is necessary for normal muscle function and positioning of nuclei
  • PMID:17676042
    a partial truncation of the C-terminal SH3 domain abrogates the interaction with DNM2 and its recruitment to the membrane tubules
  • PMID:9182667
    In skeletal muscle, amphiphysin II is concentrated around T tubules, while in brain it is concentrated in the cytomatrix beneath the plasmamembrane of axon initial segments and nodes of Ranvier
  • PMID:25051234
    all seven brain-specific BIN1 isoforms have an inserted domain that interacts with clathrin and AP2/α-adaptin (CLAP), indicating a key role for neuronal BIN1 in endocytosis

References

file:human/BIN1/BIN1-deep-research-falcon.md
Falcon deep research report for BIN1
  • Falcon corroborates the review's framing of BIN1 as a modular BAR/SH3 membrane-remodeling and scaffolding adaptor that couples membrane-curvature generation to recruitment of diverse partners across tissue-specific contexts.
    "BIN1 functions as a versatile membrane-remodeling and scaffolding protein whose modular domain architecture enables integration of membrane curvature generation with recruitment of diverse protein partners to execute tissue-specific cellular programs."
GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000054
Gene Ontology annotation based on curation of intracellular localizations of expressed fusion proteins in living cells
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10412034
Induction of apoptosis and differentiation in neuroblastoma and astrocytoma cells by the overexpression of Bin1, a novel Myc interacting protein.
PMID:10903846
Bin2, a functionally nonredundant member of the BAR adaptor gene family.
PMID:12604805
Identification and characterization of amphiphysin II as a novel cellular interaction partner of the hepatitis C virus NS5A protein.
PMID:12668730
Sorting nexin 4 and amphiphysin 2, a new partnership between endocytosis and intracellular trafficking.
PMID:15992821
A structure-based model of the c-Myc/Bin1 protein interaction shows alternative splicing of Bin1 and c-Myc phosphorylation are key binding determinants.
PMID:16275660
Identification of VCP/p97, carboxyl terminus of Hsp70-interacting protein (CHIP), and amphiphysin II interaction partners using membrane-based human proteome arrays.
PMID:16530520
The SH3 binding motif of HCV [corrected] NS5A protein interacts with Bin1 and is important for apoptosis and infectivity.
PMID:17676042
Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy.
PMID:18647389
The central proline rich region of POB1/REPS2 plays a regulatory role in epidermal growth factor receptor endocytosis by binding to 14-3-3 and SH3 domain-containing proteins.
PMID:18658220
Structure and dynamics of helix-0 of the N-BAR domain in lipid micelles and bilayers.
PMID:18985028
Hepatitis C virus infection protein network.
PMID:19004523
The membrane-tubulating potential of amphiphysin 2/BIN1 is dependent on the microtubule-binding cytoplasmic linker protein 170 (CLIP-170).
PMID:23399914
Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.
PMID:23917616
The myotubularin-amphiphysin 2 complex in membrane tubulation and centronuclear myopathies.
PMID:24169621
Elucidating novel hepatitis C virus-host interactions using combined mass spectrometry and functional genomics approaches.
PMID:24755653
Mutations in BIN1 associated with centronuclear myopathy disrupt membrane remodeling by affecting protein density and oligomerization.
PMID:25051234
Intracellular clusterin interacts with brain isoforms of the bridging integrator 1 and with the microtubule-associated protein Tau in Alzheimer's disease.
PMID:26506308
Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by Linking the Nuclear Envelope to the Actin and Microtubule Cytoskeleton.
PMID:27179792
BIN1 regulates BACE1 intracellular trafficking and amyloid-β production.
PMID:28386764
Roles of tau protein in health and disease.
PMID:28755476
Regulation of the interaction between the neuronal BIN1 isoform 1 and Tau proteins - role of the SH3 domain.
PMID:31413325
HENA, heterogeneous network-based data set for Alzheimer's disease.
PMID:32552912
Upregulation of RIN3 induces endosomal dysfunction in Alzheimer's disease.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
PMID:8782822
BIN1 is a novel MYC-interacting protein with features of a tumour suppressor.
PMID:9182667
Amphiphysin II (SH3P9; BIN1), a member of the amphiphysin/Rvs family, is concentrated in the cortical cytomatrix of axon initial segments and nodes of ranvier in brain and around T tubules in skeletal muscle.
Reactome:R-HSA-8867754
F- and N- BAR domain proteins bind the clathrin-coated pit
Reactome:R-HSA-8868230
SNX9 recruits components of the actin polymerizing machinery
Reactome:R-HSA-8868236
BAR domain proteins recruit dynamin
Reactome:R-HSA-8868648
SYNJ hydrolyze PI(4,5)P2 to PI(4)P
Reactome:R-HSA-8868651
Endophilins recruit synaptojanins to the clathrin-coated pit
Reactome:R-HSA-8868658
HSPA8-mediated ATP hydrolysis promotes vesicle uncoating
Reactome:R-HSA-8868659
Clathrin recruits auxilins to the clathrin-coated vesicle
Reactome:R-HSA-8868660
Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle
Reactome:R-HSA-8868661
Dynamin-mediated GTP hydrolysis promotes vesicle scission
Reactome:R-HSA-8869438
Dissociation of clathrin-associated proteins
Reactome:R-HSA-8871193
Dissociation of AAK1 and dephosphorylation of AP-2 mu2
Reactome:R-HSA-8871194
RAB5 and GAPVD1 bind AP-2

Suggested Questions for Experts

Q: Which BIN1 isoforms should be treated as functionally distinct for GO curation of neuronal endocytosis, skeletal-muscle T-tubule biogenesis, and nuclear/MYC-associated activities?

Suggested experts: BIN1 isoform experts, GO membrane trafficking curators

Q: Should BIN1 regulation of BACE1 abundance be curated as cargo-specific endosomal sorting rather than as direct aspartic protease inhibitor activity?

Suggested experts: APP/BACE1 trafficking experts, GO molecular-function curators

Suggested Experiments

Experiment: Rescue BIN1-null human neurons and myotubes with endogenous-level brain and muscle isoforms, then quantify clathrin/AP2/dynamin recruitment, membrane tubulation, endocytosis, and T-tubule organization.

Hypothesis: BIN1 isoform-specific inserts tune a shared BAR/SH3 membrane-remodeling module toward neuronal endocytosis or skeletal-muscle T-tubule formation.

Type: endogenous isoform-rescue membrane-remodeling assay

Experiment: Separate BIN1-BACE1 binding from endosomal sorting by comparing BAR-domain, SH3-domain, and BACE1-binding mutants for BACE1 lysosomal delivery and amyloid-beta production.

Hypothesis: BIN1 reduces amyloid-beta output primarily by BACE1 trafficking and lysosomal degradation rather than direct protease inhibition.

Type: cargo-specific trafficking separation-of-function assay

Deep Research

Falcon

(BIN1-deep-research-falcon.md)
Comprehensive Research Report on BIN1 (Bridging Integrator 1) Falcon Edison Scientific Literature 21 citations 2 artifacts 2026-06-21T07:05:19.546005
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Comprehensive Research Report on BIN1 (Bridging Integrator 1)

Gene Identity and Nomenclature

BIN1 (Bridging Integrator 1), also known as Myc box-dependent-interacting protein 1 and Amphiphysin 2, is a ubiquitously expressed membrane-remodeling protein encoded by a single gene located on human chromosome 2q14 (spooner2025benditlike pages 1-2, spooner2025benditlike pages 2-4, saha2025acomprehensivereview pages 1-2). The protein was originally discovered in 1996 through a yeast two-hybrid screen designed to identify proteins interacting with the Myc oncoprotein, with the hypothesis that such interactors might function as tumor suppressors (spooner2025benditlike pages 1-2, spooner2025benditlike pages 2-4). Subsequently, the protein was independently identified through screens targeting SH3 domain-containing proteins and through sequence homology with amphiphysin 1, establishing its classification within the amphiphysin subfamily with which it shares 55% amino acid identity and 71% similarity (spooner2025benditlike pages 1-2, spooner2025benditlike pages 2-4).

Structural Organization and Domain Architecture

The human BIN1 gene comprises 20 exons that undergo extensive alternative splicing to generate tissue-specific isoforms with distinct functional properties (spooner2025benditlike pages 1-2, spooner2025benditlike pages 2-4). The protein contains several functionally specialized domains arranged from N- to C-terminus, each contributing to BIN1's diverse cellular roles.

Domain name Exons encoding Structural features Primary molecular function Key binding partners/substrates Regulatory mechanisms
BAR domain Exons 1–10 N-terminal N-BAR; coiled-coil of three α-helices; positively charged concave membrane-binding surface; N-terminal amphipathic helix-0 inserts into bilayer; forms banana-shaped symmetric homodimers that can generate vesicles/tubules of ~220 Å radius (spooner2025benditlike pages 2-4, spooner2025benditlike pages 4-6) Senses and generates membrane curvature; drives membrane tubulation/remodeling; anchors cytoskeletal delivery tracks at curved membranes; foundational structural scaffold for t-tubules, endocytic membranes, and other membrane microdomains (zambo2024uncoveringthebin1sh3 pages 1-2, spooner2025benditlike pages 4-6, spooner2025benditlike pages 9-11) Acidic phospholipids including PI(4,5)P2 and other phosphoinositides; CLIP-170; indirectly coordinates DNM2 recruitment through overall BIN1 architecture; membrane tubules associated with CaV1.2 delivery platforms (spooner2025benditlike pages 4-6, spooner2025benditlike pages 9-11, spooner2025benditlike pages 11-12) Membrane binding is highly sensitive to lipid composition, especially PI(4,5)P2 and cholesterol; Lys164/Lys165/Lys166 in the BAR region are important for phospholipid anchoring; exon 7 within the BAR region modulates targeting specificity and may affect dynamin interaction (spooner2025benditlike pages 4-6, spooner2025benditlike pages 9-11)
PI-binding domain Exon 11 Phosphoinositide-binding segment adjacent to BAR domain; present in selected muscle-enriched and some cardiac/neuronal isoforms; can contact the SH3 domain to form a closed conformation (spooner2025benditlike pages 2-4, spooner2025benditlike pages 4-6) Enhances membrane targeting specificity for PI(4,5)P2-rich membranes; augments curvature sensing/generation; helps localize active BIN1 to tubulating membrane domains such as T-tubules (spooner2025benditlike pages 4-6) PI(4,5)P2; intramolecular interaction with SH3 domain; MTM1/myotubularin binding depends strongly on PI-domain-containing configurations in skeletal-muscle contexts (spooner2025benditlike pages 4-6, spooner2025benditlike pages 11-12) Mediates autoinhibition by binding SH3; PI(4,5)P2 binding releases the closed state and activates membrane-sculpting function; SH3 engagement by proline-rich partners can also relieve autoinhibition (spooner2025benditlike pages 4-6, spooner2025benditlike pages 11-12)
PS linker domain Exon 12 Proline/serine-rich linker region positioned between membrane- and interaction-focused regions; no definitive folded structure or discrete biochemical activity established in the cited review (spooner2025benditlike pages 2-4) Likely contributes to conformational flexibility, spacing, and/or structural integrity between domains rather than acting as a standalone catalytic or binding module (spooner2025benditlike pages 2-4) No major dedicated binding partner definitively assigned in the cited sources (spooner2025benditlike pages 2-4) Consistently retained across isoforms, suggesting selective pressure for structural or organizational importance even though its mechanistic role remains unresolved (spooner2025benditlike pages 2-4)
CLAP domain Exons 13–16 Clathrin and adaptor protein 2-binding region; exon 13 also contains an SH3-binding motif for endophilin; exons 14–15 harbor two clathrin-binding sites; variably included by alternative splicing, especially in neuronal isoforms and some cardiac isoforms containing exon 13 (spooner2025benditlike pages 2-4, spooner2025benditlike pages 6-7) Organizes endocytic machinery; promotes clathrin-coated pit/vesicle formation, membrane trafficking, and vesicle biogenesis at plasma membrane and trans-Golgi/endosomal compartments (spooner2025benditlike pages 6-7, spooner2025benditlike pages 12-14) Clathrin, AP2, endophilin; contributes to pathways involving dynamin, synaptojanin, amphiphysin-related endocytic machinery (spooner2025benditlike pages 6-7, spooner2025benditlike pages 12-14) Exon 13 can interact intramolecularly with SH3 to impose an autoinhibited closed conformation; partner binding to CLAP or SH3 can shift BIN1 toward an open active state; extensive alternative splicing tunes tissue specificity (spooner2025benditlike pages 6-7)
Myc-binding domain (MBD) Exons 17–18 C-terminal region preceding SH3; exon 18 is constitutive while exon 17 is alternatively spliced and required for full Myc-binding activity; associated with nuclear-localized isoforms (spooner2025benditlike pages 6-7) Mediates interaction with c-Myc/N-Myc; suppresses Myc-driven transformation; promotes Myc-dependent apoptosis and contributes to tumor-suppressor functions; implicated in nuclear regulatory roles (spooner2025benditlike pages 6-7, spooner2025benditlike pages 12-14) c-Myc, N-Myc; reported links to PARP1, Ku, XRCC4, and ABL1 in BIN1-associated nuclear/DNA damage regulatory functions (spooner2025benditlike pages 6-7, spooner2025benditlike pages 12-14) Functional output depends on alternative splicing of exon 17; Myc can reciprocally repress BIN1 transcription via MIZ1, creating a feedback circuit; some evidence suggests possible intramolecular MBD-SH3 interaction (spooner2025benditlike pages 6-7, spooner2025benditlike pages 7-9)
SH3 domain Exons 19–20 Conserved C-terminal Src homology 3 domain; β-barrel of 5–6 antiparallel β-strands; surface enriched in aromatic and acidic residues for proline-rich motif recognition; retained in all functional isoforms (spooner2025benditlike pages 2-4, spooner2025benditlike pages 7-9) Principal protein-protein interaction hub; recruits fission/scaffold/signaling proteins to curved membranes; central to endocytosis, T-tubule biology, actin remodeling, directed trafficking, and disease-linked interaction networks (zambo2024uncoveringthebin1sh3 pages 1-2, spooner2025benditlike pages 7-9) DNM2/dynamin-2; synaptojanin; tau via Tau 216PTPP219 region; N-WASP; ABL1; MTM1; many additional partners from interactome studies (zambo2024uncoveringthebin1sh3 pages 1-2, lasorsa2023conformationandaffinity pages 1-5, spooner2025benditlike pages 7-9) Binds proline-rich motifs; can be sequestered intramolecularly by PI or CLAP domains in autoinhibited states; release occurs upon PI(4,5)P2 engagement or partner binding; pathogenic SH3 truncation/variant states disrupt affinity networks and DNM2 recruitment (zambo2024uncoveringthebin1sh3 pages 1-2, spooner2025benditlike pages 4-6, lasorsa2023conformationandaffinity pages 1-5)

Table: This table summarizes the major BIN1 protein domains, the exons that encode them, their structural properties, molecular functions, binding partners, and known regulatory mechanisms. It is useful for linking BIN1 isoform architecture to its membrane-remodeling, endocytic, nuclear, and disease-relevant functions.

The N-terminal BAR (Bin/Amphiphysin/Rvs) domain (exons 1-10) constitutes the fundamental membrane-binding module of BIN1 (spooner2025benditlike pages 2-4, spooner2025benditlike pages 4-6). Structurally, the BAR domain adopts a coiled-coil architecture composed of three α-helices that pack tightly together following a characteristic knob-socket pattern of nonpolar residue interactions (spooner2025benditlike pages 4-6). This domain forms symmetrical banana-shaped homodimers with a positively charged concave surface that engages negatively charged phospholipid headgroups through electrostatic interactions (spooner2025benditlike pages 2-4, spooner2025benditlike pages 4-6). The N-terminal region contains a disordered segment that forms an amphipathic helix (helix-0) upon insertion into the lipid bilayer, enhancing membrane curvature generation (spooner2025benditlike pages 4-6). These BAR domain dimers can generate vesicular and tubular structures with an approximate radius of 220 Å, though varying dimer arrangements along membrane surfaces produce structures of diverse dimensions (spooner2025benditlike pages 4-6).

Adjacent to the BAR domain, exon 11 encodes a phosphoinositide (PI)-binding domain present in muscle-enriched and select cardiac/neuronal isoforms (spooner2025benditlike pages 2-4, spooner2025benditlike pages 4-6). This domain specifically recognizes phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], significantly augmenting membrane interaction specificity and curvature generation (spooner2025benditlike pages 4-6). The PI domain participates in an autoinhibitory regulatory mechanism whereby it can bind intramolecularly to the C-terminal SH3 domain, shifting BIN1 into a closed, conformationally restrained state in which membrane curvature induction is substantially inhibited (spooner2025benditlike pages 4-6, spooner2025benditlike pages 11-12). Membrane-embedded PI(4,5)P2 triggers a conformational switch by engaging the PI domain with higher affinity than the SH3 domain, promoting adoption of an open, active conformation that spatially restricts BIN1's scaffolding activities to PI(4,5)P2-enriched membrane microdomains (spooner2025benditlike pages 4-6, spooner2025benditlike pages 11-12).

Exon 12 contains a proline- and serine-rich linker region (PS domain) consistently retained across all isoforms, suggesting importance for proper protein folding and structural integrity, though its precise functional role remains to be fully elucidated (spooner2025benditlike pages 2-4).

The CLAP (Clathrin and Adaptor Protein 2 binding) domain (exons 13-16) exhibits pronounced variability across isoforms through alternative splicing (spooner2025benditlike pages 2-4, spooner2025benditlike pages 6-7). Exon 13 contains an SH3-binding motif for endophilin interaction, while exons 14-15 harbor two distinct clathrin-binding sites (spooner2025benditlike pages 6-7). This domain orchestrates endocytic processes through recruitment and assembly of protein complexes within clathrin-coated pits, facilitating both plasma membrane endocytosis and vesicle biogenesis at the trans-Golgi network (spooner2025benditlike pages 6-7, spooner2025benditlike pages 12-14). Similar to the PI domain, exon 13 can interact intramolecularly with the SH3 domain to impose an autoinhibited closed conformation, with partner binding to either CLAP or SH3 shifting BIN1 toward an open active state (spooner2025benditlike pages 6-7).

The Myc-binding domain (MBD, exons 17-18) mediates BIN1's tumor suppressor functions through direct interaction with c-Myc and N-Myc transcription factors (spooner2025benditlike pages 2-4, spooner2025benditlike pages 6-7). While exon 18 is consistently retained, exon 17 displays selective inclusion and is critically required for Myc-binding functionality (spooner2025benditlike pages 6-7, spooner2025benditlike pages 7-9). Nuclear-localized BIN1 isoforms containing this domain bind the N-terminal regulatory domain of Myc, inhibiting Myc-mediated transcriptional activity and neoplastic transformation while promoting Myc-dependent apoptosis (spooner2025benditlike pages 6-7, spooner2025benditlike pages 7-9).

The C-terminal SH3 (Src Homology 3) domain (exons 19-20) serves as BIN1's primary molecular interface for protein-protein interactions (spooner2025benditlike pages 2-4, spooner2025benditlike pages 7-9). This domain adopts a characteristic β-barrel configuration composed of five to six anti-parallel β-strands, with a surface enriched in aromatic and carboxylic acid residues that recognize and bind proline-rich motifs in partner proteins (spooner2025benditlike pages 7-9). The SH3 domain is invariably retained across all functional BIN1 isoforms, and mutations within this region are causally linked to centronuclear myopathy, underscoring its physiological significance (zambo2024uncoveringthebin1sh3 pages 1-2, spooner2025benditlike pages 7-9).

Primary Molecular Functions

Membrane Curvature Sensing and Generation

BIN1's fundamental molecular function centers on sensing and generating membrane curvature, a property that underpins its diverse cellular roles (zambo2024uncoveringthebin1sh3 pages 1-2, spooner2025benditlike pages 4-6). The BAR domain constitutes the primary determinant of this membrane-sculpting capacity, engaging membranes through electrostatic interactions and mechanically deforming lipid bilayers into highly curved tubular and vesicular structures (spooner2025benditlike pages 2-4, spooner2025benditlike pages 4-6). This membrane remodeling activity is exquisitely sensitive to lipid composition, particularly requiring PI(4,5)P2 for optimal tubulation, with activity increasing to a plateau at approximately 3% PI(4,5)P2 concentration (spooner2025benditlike pages 4-6). Additionally, membrane cholesterol content is critical for supporting the high degree of curvature found within tubules (spooner2025benditlike pages 4-6).

Specific lysine residues (Lys164, Lys165, Lys166) located within the BAR domain have been identified as critical for anchoring BIN1 to negatively charged membrane phospholipids (spooner2025benditlike pages 9-11). When these lysines are mutated to negatively charged amino acids in experimental systems, BIN1 redistributes from membrane-associated structures to a diffuse cytosolic pattern with complete loss of membrane tubulation capability (spooner2025benditlike pages 9-11).

The membrane curvature-generating function is further modulated by the PI domain in isoforms where it is present. PI(4,5)P2 binding by this domain not only enhances membrane targeting specificity but also regulates BIN1's conformational state through the autoinhibitory mechanism described above, ensuring that active membrane sculpting is spatially restricted to appropriate cellular locations (spooner2025benditlike pages 4-6, spooner2025benditlike pages 11-12).

Adapter and Scaffolding Functions

Beyond its direct membrane-remodeling activities, BIN1 functions as a versatile molecular scaffold that organizes multi-protein complexes at curved membranes (spooner2025benditlike pages 2-4, spooner2025benditlike pages 7-9). The SH3 domain mediates the majority of BIN1's documented protein-protein interactions, engaging numerous partners spanning diverse cellular functions (zambo2024uncoveringthebin1sh3 pages 1-2, spooner2025benditlike pages 7-9). This scaffolding capacity enables BIN1 to couple membrane remodeling with recruitment of enzymatic activities, structural proteins, and signaling molecules required for specialized cellular processes.

Protein partner Domain of BIN1 involved in interaction Cellular pathway/process Functional consequence of interaction Tissue/cell type specificity
Dynamin-2 (DNM2) Primarily SH3 domain; BAR domain functionally cooperates by generating curved membranes Clathrin-mediated endocytosis, vesicle scission, T-tubule biogenesis BIN1 recruits DNM2 to curved membranes; this supports vesicle scission in endocytosis and contributes to T-tubule formation/remodeling. Loss of SH3-mediated recruitment is central to BIN1-related centronuclear myopathy (zambo2024uncoveringthebin1sh3 pages 1-2, spooner2025benditlike pages 7-9) Broadly relevant; especially skeletal muscle and cardiac muscle, also endocytic membranes in other cells (zambo2024uncoveringthebin1sh3 pages 1-2, spooner2025benditlike pages 12-14)
Tau (MAPT) SH3 domain binds Tau proline-rich motif Alzheimer-related tau biology, tau aggregation/propagation Direct BIN1-Tau binding is modulated by Tau phosphorylation; BIN1 cleavage fragment BIN1(1-277) can bind Tau and accelerate aggregation while enhancing clathrin-mediated endocytosis-dependent propagation (lasorsa2023conformationandaffinity pages 1-5, zhang2024bridgingintegrator1 pages 1-2) Neurons/brain; especially relevant to Alzheimer’s disease (zhang2024bridgingintegrator1 pages 1-2, saha2025acomprehensivereview pages 1-2)
c-Myc / N-Myc Myc-binding domain (MBD; exons 17-18) Nuclear signaling, cell-cycle control, tumor suppression, apoptosis BIN1 binds Myc and suppresses Myc-driven transcriptional and transforming activity; supports Myc-dependent apoptosis and broader tumor suppressor functions (spooner2025benditlike pages 6-7, spooner2025benditlike pages 12-14) Nuclear isoforms in proliferative contexts; cancer-relevant tissues, and some cardiac/brain cell contexts with nuclear BIN1 isoforms (spooner2025benditlike pages 6-7, spooner2025benditlike pages 7-9)
Clathrin CLAP domain (especially exons 14-15); neuronal isoforms may be particularly relevant Clathrin-mediated endocytosis, vesicle biogenesis BIN1 helps assemble clathrin-coated pits/vesicles and participates in membrane budding and trafficking from plasma membrane, Golgi, and endosomes (spooner2025benditlike pages 6-7, spooner2025benditlike pages 12-14) Strongly established in neuronal/brain isoforms; likely also relevant in other tissues with CLAP-containing isoforms (spooner2025benditlike pages 2-4, spooner2025benditlike pages 12-14)
AP2 (Adaptor protein 2) CLAP domain, especially exon 13 Clathrin-mediated endocytosis and membrane trafficking BIN1 association with AP2 helps coordinate endocytic complex assembly and cargo internalization at the plasma membrane (spooner2025benditlike pages 6-7, spooner2025benditlike pages 12-14) Best established in neuronal/endocytic contexts; potentially relevant in cardiac isoforms containing exon 13 (spooner2025benditlike pages 6-7)
N-WASP SH3 domain Actin remodeling, membrane-cytoskeleton coupling, directed trafficking BIN1-N-WASP interaction promotes ARP2/3-mediated actin polymerization and helps anchor actin to BIN1-associated membranes, supporting tubulation and membrane organization (spooner2025benditlike pages 7-9, spooner2025benditlike pages 9-11) Neuronal and muscle contexts; implicated in t-tubule anchoring and membrane remodeling (spooner2025benditlike pages 9-11)
CaV1.2 (L-type calcium channel) Not mapped to a single motif with the same precision as SH3 ligands; interaction/functionally linked to BAR-dependent membrane platforms and BIN1 scaffolding Excitation-contraction coupling, targeted ion-channel trafficking BIN1 colocalizes and co-immunoprecipitates with CaV1.2, promotes microtubule-dependent delivery to T-tubules, and supports channel clustering at dyads (spooner2025benditlike pages 9-11, spooner2025benditlike pages 12-14) Cardiac myocytes; t-tubule sarcolemma (spooner2025benditlike pages 9-11, spooner2025benditlike pages 14-15)
RyR2 (ryanodine receptor 2) Precise binding interface not yet clearly defined; likely scaffolded indirectly within BIN1-organized dyads Excitation-contraction coupling, dyad organization BIN1 supports RyR2 localization to dyads and proper junctional organization; BIN1 loss disrupts RyR2 positioning and calcium release synchrony (spooner2025benditlike pages 9-11, spooner2025benditlike pages 12-14) Cardiac myocytes (spooner2025benditlike pages 9-11, spooner2025benditlike pages 14-15)
CLIP-170 BAR domain Microtubule anchoring, directed trafficking, membrane remodeling BIN1-BAR interaction with CLIP-170 anchors microtubules to membrane tubules, enabling targeted delivery of cargo such as CaV1.2 to T-tubules (spooner2025benditlike pages 4-6, spooner2025benditlike pages 9-11) Cardiac myocytes and cultured cells; likely broader relevance in membrane-directed trafficking (spooner2025benditlike pages 9-11, spooner2025benditlike pages 12-14)
MTM1 (myotubularin 1) BAR and SH3 domains; interaction strongly influenced by PI domain-dependent conformation Phosphoinositide-regulated membrane remodeling, T-tubule growth MTM1 cooperates with BIN1 to promote elongated tubules in muscle; interaction is favored when BIN1 adopts an open conformation and links phosphoinositide homeostasis to membrane tubulation (spooner2025benditlike pages 11-12) Strongly established in skeletal muscle; direct interaction less clear for exon 11-lacking cardiac isoforms, though MTM1 still influences cardiac t-tubule growth (spooner2025benditlike pages 11-12)
RIN2 Specific BIN1 interaction interface not yet fully resolved in cited source Early endosome targeting, Rab5-associated endosomal trafficking RIN2 recruits BIN1 to RAB5-positive early endosomes, identifying a neuron-specific endosomal localization mechanism linked to Alzheimer-relevant trafficking pathways (wei2026interactomemappingin pages 1-3) Human excitatory neurons / neuron-specific interactome context (wei2026interactomemappingin pages 1-3)

Table: This table summarizes major BIN1 protein interaction partners, the BIN1 domains involved, and the pathways they influence. It is useful for connecting BIN1’s membrane-remodeling scaffold function to tissue-specific roles in endocytosis, muscle excitation-contraction coupling, and Alzheimer’s disease biology.

A prototypical example is BIN1's role in coordinating membrane fission during endocytosis. The BAR domain generates initial membrane curvature while the SH3 domain recruits dynamin-2 (DNM2), a GTPase whose oligomerization and enzymatic activity drive vesicle scission (zambo2024uncoveringthebin1sh3 pages 1-2, spooner2025benditlike pages 7-9, spooner2025benditlike pages 12-14). This spatial and temporal coupling of curvature generation and membrane fission is essential for efficient endocytic vesicle formation (zambo2024uncoveringthebin1sh3 pages 1-2).

Similarly, in striated muscle, BIN1 organizes elaborate protein complexes at specialized membrane microdomains. The BAR domain binds the microtubule-associated protein CLIP-170, anchoring microtubule plus-ends to membrane tubules and enabling targeted delivery of cargo proteins such as CaV1.2 calcium channels to transverse tubules (t-tubules) (spooner2025benditlike pages 4-6, spooner2025benditlike pages 9-11, spooner2025benditlike pages 12-14). Simultaneously, the SH3 domain engages N-WASP to promote actin polymerization, linking t-tubules to the sarcomeric cytoskeleton (spooner2025benditlike pages 7-9, spooner2025benditlike pages 9-11).

Cellular Localization

BIN1's cellular distribution is highly context-dependent, reflecting both isoform-specific properties and the dynamic membrane-remodeling processes in which it participates (spooner2025benditlike pages 1-2, spooner2025benditlike pages 2-4).

Plasma Membrane and T-Tubule Localization

In striated muscle cells (both cardiac and skeletal), BIN1 exhibits specific localization to t-tubules, which are sarcolemmal invaginations that penetrate deep into the myocyte interior (spooner2025benditlike pages 1-2, spooner2025benditlike pages 7-9, spooner2025benditlike pages 9-11). These structures are essential for rapid propagation of action potentials throughout the cell volume and proper excitation-contraction coupling (spooner2025benditlike pages 7-9, spooner2025benditlike pages 9-11). BIN1 colocalizes at t-tubules with voltage-gated CaV1.2 calcium channels and is positioned adjacent to type 2 ryanodine receptors (RyR2) on the junctional sarcoplasmic reticulum, forming dyadic junctions where calcium influx through CaV1.2 triggers calcium release from RyR2 (spooner2025benditlike pages 7-9, spooner2025benditlike pages 9-11).

In neurons, BIN1 localizes to nerve terminals and synaptic regions where it participates in synaptic vesicle endocytosis and neurotransmitter receptor trafficking (spooner2025benditlike pages 7-9, spooner2025benditlike pages 12-14).

Endosomal Compartments

BIN1 is found associated with various endosomal compartments throughout the endocytic pathway (spooner2025benditlike pages 6-7, spooner2025benditlike pages 12-14). At clathrin-coated pits, CLAP domain-containing isoforms organize endocytic machinery and coordinate vesicle formation (spooner2025benditlike pages 6-7, spooner2025benditlike pages 12-14). Recent neuron-specific interactome studies identified RIN2 as a BIN1 binding partner that recruits BIN1 to RAB5-positive early endosomes, revealing neuron-specific endosomal targeting mechanisms linked to Alzheimer-relevant trafficking pathways (wei2026interactomemappingin pages 1-3).

Changes in BIN1 expression levels have been shown to alter endosomal morphology and trafficking dynamics, with BIN1 modulation associated with enlarged endosomes and altered protein trafficking patterns—early hallmarks of Alzheimer's disease that also occur in aging hearts (spooner2025benditlike pages 12-14).

Nuclear Localization

In certain cellular contexts, particularly in proliferative cells and specific isoforms containing the full Myc-binding domain, BIN1 exhibits nuclear localization (spooner2025benditlike pages 1-2, spooner2025benditlike pages 6-7, spooner2025benditlike pages 7-9). Nuclear BIN1 directly interacts with and regulates transcription factors, most notably c-Myc, executing tumor suppressor functions through transcriptional repression and promotion of apoptosis in cells with DNA damage (spooner2025benditlike pages 6-7, spooner2025benditlike pages 7-9, spooner2025benditlike pages 12-14).

Biochemical Pathways and Signaling Networks

Clathrin-Mediated Endocytosis

BIN1 plays a central coordinating role in clathrin-mediated endocytosis (CME), the predominant pathway for internalization of plasma membrane receptors and extracellular material (spooner2025benditlike pages 6-7, spooner2025benditlike pages 12-14). Through its CLAP domain, BIN1 recruits and organizes core endocytic machinery including clathrin, adaptor protein 2 (AP2), and accessory proteins such as endophilin (spooner2025benditlike pages 6-7, spooner2025benditlike pages 12-14). The BAR domain generates membrane curvature at nascent endocytic pits, while the SH3 domain recruits dynamin-2 to execute membrane fission and vesicle release (zambo2024uncoveringthebin1sh3 pages 1-2, spooner2025benditlike pages 12-14).

This endocytic function extends beyond constitutive cargo internalization to include specialized roles in synaptic vesicle recycling at neuronal terminals, receptor downregulation, and pathological processes such as tau aggregate uptake in Alzheimer's disease (zhang2024bridgingintegrator1 pages 1-2, spooner2025benditlike pages 12-14). Notably, isoforms containing the CLAP domain have been found to exert direct negative regulatory effects on endocytic flux, with BIN1 expression changes associated with "endosomal traffic jams" featuring enlarged endosomes and altered protein trafficking (spooner2025benditlike pages 12-14).

Excitation-Contraction Coupling in Striated Muscle

In cardiac and skeletal muscle, BIN1 functions as an essential architect of the t-tubule system and dyadic junctions that mediate excitation-contraction coupling (spooner2025benditlike pages 7-9, spooner2025benditlike pages 9-11). BIN1's membrane-sculpting capacity drives t-tubule biogenesis, generating the tubular sarcolemmal invaginations that allow electrical signals to rapidly reach the cell interior (spooner2025benditlike pages 7-9, spooner2025benditlike pages 9-11).

Beyond structural roles, BIN1 coordinates the spatial organization and targeted delivery of key calcium-handling proteins (spooner2025benditlike pages 9-11, spooner2025benditlike pages 12-14). Through interaction with CLIP-170, BIN1 anchors microtubules to t-tubule membranes, establishing tracks for directed trafficking of CaV1.2 channels to specific t-tubule locations (spooner2025benditlike pages 9-11, spooner2025benditlike pages 12-14). This directed delivery results in clusters of CaV1.2 channels around delivery points that can cooperate through local gating interactions, amplifying calcium influx signals (spooner2025benditlike pages 12-14). BIN1 also supports RyR2 localization to dyads and proper junctional organization between t-tubules and sarcoplasmic reticulum, with BIN1 loss disrupting RyR2 positioning and calcium release synchrony (spooner2025benditlike pages 9-11, spooner2025benditlike pages 12-14).

The phosphoinositide phosphatase myotubularin 1 (MTM1) cooperates with BIN1 in regulating t-tubule development (spooner2025benditlike pages 11-12). MTM1 promotes PI(4,5)P2 formation by metabolizing PI(3)P and PI(3,5)P2, and its interaction with BIN1 is critical for producing elongated, reticulated tubular networks in muscle cells (spooner2025benditlike pages 11-12). This partnership links phosphoinositide homeostasis to membrane tubulation, with MTM1's catalytic activity required for BIN1-dependent t-tubule growth (spooner2025benditlike pages 11-12).

Myc Signaling and Tumor Suppression

BIN1 was originally identified as a tumor suppressor that binds to and inhibits the Myc oncoprotein (spooner2025benditlike pages 1-2, spooner2025benditlike pages 6-7). Nuclear-localized BIN1 isoforms containing exons 17-18 interact with the N-terminal regulatory domain of c-Myc and N-Myc, suppressing their transcriptional activity and inhibiting neoplastic transformation (spooner2025benditlike pages 6-7, spooner2025benditlike pages 7-9). Concurrently, BIN1 promotes Myc-dependent apoptosis, contributing to elimination of cells with DNA damage that pose cancer risk (spooner2025benditlike pages 6-7, spooner2025benditlike pages 7-9).

This relationship involves a reciprocal regulatory circuit wherein Myc can repress BIN1 expression by blocking its transcriptional activation by MIZ1 (MYC interacting zinc finger transcription factor 1), establishing a homeostatic balance where perturbation of either component disrupts expression profiles and downstream signaling cascades (spooner2025benditlike pages 7-9). BIN1 also interacts with DNA repair proteins including PARP1, Ku, and XRCC4, inhibiting DNA repair after sufficient damage to ensure that damaged cells undergo apoptosis rather than persist with genomic instability (spooner2025benditlike pages 12-14).

Tau Pathology in Alzheimer's Disease

BIN1 has emerged as the second most significant genetic risk factor for late-onset Alzheimer's disease after APOE (saha2025acomprehensivereview pages 1-2, hu2025newinsightson pages 1-6, zhang2024bridgingintegrator1 pages 1-2). The protein directly interacts with tau via SH3 domain binding to tau's proline-rich region (specifically the 216PTPP219 motif), and this interaction is modulated by tau phosphorylation (lasorsa2023conformationandaffinity pages 1-5).

Recent mechanistic studies have revealed that neuronal BIN1 is cleaved by the cysteine protease legumain at residues N277 and N288, generating a BIN1(1-277) fragment detectable in brain tissues from Alzheimer's disease patients (zhang2024bridgingintegrator1 pages 1-2). This fragment retains the ability to interact with tau and accelerates tau aggregation (zhang2024bridgingintegrator1 pages 1-2). Furthermore, the BIN1(1-277) fragment promotes propagation of tau aggregates by enhancing clathrin-mediated endocytosis, facilitating uptake and transcellular spread of pathological tau (zhang2024bridgingintegrator1 pages 1-2). Experimental overexpression of this fragment in tau transgenic mice facilitates tau pathology propagation and induces cognitive deficits, while blocking endogenous BIN1 cleavage ameliorates tau pathology and behavioral deficits (zhang2024bridgingintegrator1 pages 1-2).

Beyond this pathological cleavage, BIN1 participates in normal endosomal trafficking processes relevant to Alzheimer's pathogenesis (saha2025acomprehensivereview pages 1-2, wei2026interactomemappingin pages 1-3). BIN1 controls membrane curvature and participates in clathrin-dependent endocytosis, with changes in BIN1 expression levels impairing endocytic flux likely due to problems with vesicle scission and trafficking (saha2025acomprehensivereview pages 1-2). The recent identification of RIN2 as a neuron-specific BIN1 interactor that recruits BIN1 to RAB5-positive early endosomes suggests additional mechanisms whereby BIN1 modulates endosomal processes linked to Alzheimer's disease etiology (wei2026interactomemappingin pages 1-3).

Isoform-Specific Functional Specialization

The extensive alternative splicing of BIN1's 20 exons generates tissue-specific isoforms with distinct functional properties and cellular distributions (spooner2025benditlike pages 1-2, spooner2025benditlike pages 2-4, hu2025newinsightson pages 1-6). In the brain, neuronal isoforms (containing exons 13-16 encoding the full CLAP domain) and glial isoforms (lacking these exons) are differentially expressed and implicated in distinct aspects of Alzheimer's pathology (saha2025acomprehensivereview pages 1-2, hu2025newinsightson pages 1-6). In Alzheimer's disease, there is a significant shift in isoform expression characterized by upregulation of shorter glial-specific isoforms and downregulation of longer neuronal isoforms, with this isoform imbalance interfering with neuronal function and contributing to disease pathogenesis (saha2025acomprehensivereview pages 1-2, hu2025newinsightson pages 1-6).

In cardiac tissue, isoform patterns differ across mammalian species but generally include ubiquitous isoforms (9, 10) and muscle-enriched isoforms, with some species expressing PI domain-containing isoforms (4, 8, 13) that confer enhanced curvature generation and conformational regulation (spooner2025benditlike pages 1-2, spooner2025benditlike pages 2-4). Cardiac-specific isoform 6 (BIN1+13+17) has been shown to uniquely restore t-tubule microfolding in BIN1-deficient cardiomyocytes, highlighting isoform-specific functional specialization even among closely related variants (spooner2025benditlike pages 9-11).

Disease Relevance

Mutations and altered expression of BIN1 are causally linked to multiple human diseases (zambo2024uncoveringthebin1sh3 pages 1-2, saha2025acomprehensivereview pages 1-2, zhang2024bridgingintegrator1 pages 1-2). Autosomal recessive centronuclear myopathy results from BIN1 mutations in the BAR domain that prevent membrane-remodeling function, or from truncations of the SH3 domain that eliminate DNM2 recruitment while preserving membrane tubulation capacity (zambo2024uncoveringthebin1sh3 pages 1-2). Reduced BIN1 expression characterizes human heart failure, where decreased levels correlate with CaV1.2 mislocalization, RyR2 dysfunction, t-tubule disruption, and impaired calcium handling (spooner2025benditlike pages 12-14, spooner2025benditlike pages 14-15). In Alzheimer's disease, BIN1 genetic variants confer disease risk through effects on isoform expression and splicing patterns, while legumain-mediated BIN1 cleavage actively promotes tau pathology progression (saha2025acomprehensivereview pages 1-2, hu2025newinsightson pages 1-6, zhang2024bridgingintegrator1 pages 1-2). Loss of BIN1 expression is frequent in human malignancies, consistent with its tumor suppressor functions through Myc inhibition (spooner2025benditlike pages 6-7, spooner2025benditlike pages 7-9).

Conclusion

BIN1 functions as a versatile membrane-remodeling and scaffolding protein whose modular domain architecture enables integration of membrane curvature generation with recruitment of diverse protein partners to execute tissue-specific cellular programs. Through its BAR domain-mediated membrane sculpting, PI domain-regulated targeting, CLAP domain-organized endocytosis, Myc-binding domain nuclear functions, and SH3 domain protein interaction networks, BIN1 orchestrates critical processes ranging from t-tubule biogenesis in muscle to endocytic trafficking in neurons to tumor suppression in proliferative cells. The extensive alternative splicing that generates tissue-specific isoform repertoires provides an additional regulatory layer that tunes BIN1 function to particular cellular contexts. Dysregulation of BIN1 expression, splicing, or post-translational processing contributes to diverse human pathologies including centronuclear myopathy, heart failure, Alzheimer's disease, and cancer, highlighting the protein's essential physiological roles and therapeutic potential.

References

  1. (spooner2025benditlike pages 1-2): Heather C. Spooner and Rose E. Dixon. Bend it like bin1: how a membrane-curving adaptor protein shapes cardiac physiology. Jul 2025. URL: https://doi.org/10.1152/ajpheart.00198.2025, doi:10.1152/ajpheart.00198.2025. This article has 2 citations.

  2. (spooner2025benditlike pages 2-4): Heather C. Spooner and Rose E. Dixon. Bend it like bin1: how a membrane-curving adaptor protein shapes cardiac physiology. Jul 2025. URL: https://doi.org/10.1152/ajpheart.00198.2025, doi:10.1152/ajpheart.00198.2025. This article has 2 citations.

  3. (saha2025acomprehensivereview pages 1-2): Trina Saha and Dipanjan Karati. A comprehensive review on novel opportunities for alzheimer therapy by targeting bin1. Egyptian Journal of Medical Human Genetics, Aug 2025. URL: https://doi.org/10.1186/s43042-025-00759-8, doi:10.1186/s43042-025-00759-8. This article has 4 citations and is from a peer-reviewed journal.

  4. (spooner2025benditlike pages 4-6): Heather C. Spooner and Rose E. Dixon. Bend it like bin1: how a membrane-curving adaptor protein shapes cardiac physiology. Jul 2025. URL: https://doi.org/10.1152/ajpheart.00198.2025, doi:10.1152/ajpheart.00198.2025. This article has 2 citations.

  5. (zambo2024uncoveringthebin1sh3 pages 1-2): Boglarka Zambo, Evelina Edelweiss, Bastien Morlet, Luc Negroni, Mátyás Pajkos, Zsuzsanna Dosztányi, Soren Ostergaard, Gilles Trave, Jocelyn Laporte, and Gergo Gogl. Uncovering the bin1-sh3 interactome underpinning centronuclear myopathy. eLife, Apr 2024. URL: https://doi.org/10.1101/2023.02.14.528471, doi:10.1101/2023.02.14.528471. This article has 12 citations and is from a domain leading peer-reviewed journal.

  6. (spooner2025benditlike pages 9-11): Heather C. Spooner and Rose E. Dixon. Bend it like bin1: how a membrane-curving adaptor protein shapes cardiac physiology. Jul 2025. URL: https://doi.org/10.1152/ajpheart.00198.2025, doi:10.1152/ajpheart.00198.2025. This article has 2 citations.

  7. (spooner2025benditlike pages 11-12): Heather C. Spooner and Rose E. Dixon. Bend it like bin1: how a membrane-curving adaptor protein shapes cardiac physiology. Jul 2025. URL: https://doi.org/10.1152/ajpheart.00198.2025, doi:10.1152/ajpheart.00198.2025. This article has 2 citations.

  8. (spooner2025benditlike pages 6-7): Heather C. Spooner and Rose E. Dixon. Bend it like bin1: how a membrane-curving adaptor protein shapes cardiac physiology. Jul 2025. URL: https://doi.org/10.1152/ajpheart.00198.2025, doi:10.1152/ajpheart.00198.2025. This article has 2 citations.

  9. (spooner2025benditlike pages 12-14): Heather C. Spooner and Rose E. Dixon. Bend it like bin1: how a membrane-curving adaptor protein shapes cardiac physiology. Jul 2025. URL: https://doi.org/10.1152/ajpheart.00198.2025, doi:10.1152/ajpheart.00198.2025. This article has 2 citations.

  10. (spooner2025benditlike pages 7-9): Heather C. Spooner and Rose E. Dixon. Bend it like bin1: how a membrane-curving adaptor protein shapes cardiac physiology. Jul 2025. URL: https://doi.org/10.1152/ajpheart.00198.2025, doi:10.1152/ajpheart.00198.2025. This article has 2 citations.

  11. (lasorsa2023conformationandaffinity pages 1-5): Alessia Lasorsa, Krishnendu Bera, Idir Malki, Elian Dupré, François-Xavier Cantrelle, Hamida Merzougui, Davy Sinnaeve, Xavier Hanoulle, Jozef Hritz, and Isabelle Landrieu. Conformation and affinity modulations by multiple phosphorylation occurring in the bin1 sh3 domain binding site of the tau protein proline-rich region. Biochemistry, 62:1631-1642, May 2023. URL: https://doi.org/10.1021/acs.biochem.2c00717, doi:10.1021/acs.biochem.2c00717. This article has 11 citations and is from a peer-reviewed journal.

  12. (zhang2024bridgingintegrator1 pages 1-2): Xingyu Zhang, Li Zou, Lingyuan Tang, Min Xiong, Xiao-Xin Yan, Lanxia Meng, Guiqin Chen, Jing Xiong, Shuke Nie, Zhaohui Zhang, Qiang Chen, and Zhentao Zhang. Bridging integrator 1 fragment accelerates tau aggregation and propagation by enhancing clathrin-mediated endocytosis in mice. PLOS Biology, 22:e3002470, Jan 2024. URL: https://doi.org/10.1371/journal.pbio.3002470, doi:10.1371/journal.pbio.3002470. This article has 17 citations and is from a highest quality peer-reviewed journal.

  13. (spooner2025benditlike pages 14-15): Heather C. Spooner and Rose E. Dixon. Bend it like bin1: how a membrane-curving adaptor protein shapes cardiac physiology. Jul 2025. URL: https://doi.org/10.1152/ajpheart.00198.2025, doi:10.1152/ajpheart.00198.2025. This article has 2 citations.

  14. (wei2026interactomemappingin pages 1-3): Xiaomu Wei, Katie Munechika, Yu Sun, Yuansong Wan, Tianyu Xia, Yuan Hou, Wenqiang Song, Kumar Yugandhar, Yiwen Wang, Se-In Lee, Zhengdong Sha, Yadi Zhou, Weixi Feng, Jingjie Zhu, Yuliang Tang, Wenjie Luo, Feixiong Cheng, Li Gan, and Haiyuan Yu. Interactome mapping in human excitatory neurons reveals novel risk genes and pathways in alzheimer’s disease. bioRxiv, Mar 2026. URL: https://doi.org/10.64898/2026.03.14.711835, doi:10.64898/2026.03.14.711835. This article has 0 citations.

  15. (hu2025newinsightson pages 1-6): Min Hu, Sahar Esmaeeli, Lindsay Stolzenburg, Mariam Jouni, Eugene Nyamugenda, Peter Reinhardt, Lamiaa Bahnassawy, Laura Gasparini, Jeffrey F. Waring, and Aparna Vasanthakumar. New insights on bridging integrator 1 protein isoforms as a risk increasing gene in alzheimer’s disease. bioRxiv, Apr 2025. URL: https://doi.org/10.1101/2025.03.31.646439, doi:10.1101/2025.03.31.646439. This article has 0 citations.

Artifacts

Citations

  1. spooner2025benditlike pages 4-6
  2. spooner2025benditlike pages 2-4
  3. spooner2025benditlike pages 6-7
  4. spooner2025benditlike pages 7-9
  5. spooner2025benditlike pages 9-11
  6. spooner2025benditlike pages 11-12
  7. wei2026interactomemappingin pages 1-3
  8. spooner2025benditlike pages 12-14
  9. lasorsa2023conformationandaffinity pages 1-5
  10. saha2025acomprehensivereview pages 1-2
  11. spooner2025benditlike pages 1-2
  12. spooner2025benditlike pages 14-15
  13. hu2025newinsightson pages 1-6
  14. PI(4,5)P2
  15. https://doi.org/10.1152/ajpheart.00198.2025,
  16. https://doi.org/10.1186/s43042-025-00759-8,
  17. https://doi.org/10.1101/2023.02.14.528471,
  18. https://doi.org/10.1021/acs.biochem.2c00717,
  19. https://doi.org/10.1371/journal.pbio.3002470,
  20. https://doi.org/10.64898/2026.03.14.711835,
  21. https://doi.org/10.1101/2025.03.31.646439,

📚 Additional Documentation

Notes

(BIN1-notes.md)

BIN1 curation notes

2026-06-19

  • Deep-research attempt with just deep-research-falcon human BIN1 --fallback perplexity-lite timed out after 180 seconds with no generated research artifact, so this manual review uses cached UniProt, GOA, PANTHER family, and publication evidence.
  • BIN1 encodes amphiphysin II, a BAR-domain and SH3-domain membrane remodeling/adaptor protein with major brain and skeletal-muscle isoforms. UniProt frames the core function as control of plasma membrane curvature, membrane shaping/remodeling, T-tubule formation, vesicle sorting, BACE1 trafficking, and actin remodeling.
  • The BAR-domain membrane-curvature function is the core molecular function. BAR domains "generate and sense membrane curvature" by binding negatively charged membranes PMID:18658220, and BIN1 N-BAR disease mutants impair membrane tubulation in vivo and in vitro PMID:24755653.
  • Muscle T-tubule and neuronal endocytic-domain localization are well supported. Amphiphysin II/BIN1 is concentrated around T tubules in skeletal muscle and beneath the plasma membrane at axon initial segments and nodes of Ranvier in brain PMID:9182667.
  • The SH3-domain adaptor function is core for endocytosis and muscle membrane remodeling. BIN1 mutations can disrupt DNM2 interaction and membrane tubule recruitment, supporting dynamin/GTPase-binding annotations PMID:17676042.
  • BACE1 trafficking and amyloid-beta production annotations are real but non-core. The cached abstract says BIN1 depletion increases BACE1 by impaired endosomal trafficking and reduced lysosomal degradation PMID:27179792, which supports cargo trafficking rather than direct aspartic protease inhibitor activity.
  • Tau binding is supported and Alzheimer-relevant, but I kept it non-core because it is a context-specific disease/pathology interaction rather than the primary BAR-domain membrane remodeling role PMID:25051234.
  • Nuclear/MYC/transcription/cell-cycle/apoptosis annotations are retained as non-core because they represent tumor-suppressor or isoform-specific literature rather than the main membrane-remodeling function.
  • Generic protein binding annotations are over-annotated; more informative binding terms such as phospholipid binding, clathrin binding, GTPase binding, and actin filament binding are retained where supported.

2026-06-20 second-pass audit

The second-pass audit added manual reference_review metadata for BIN1 membrane-curvature/BAR-domain evidence, disease-mutant membrane tubulation evidence, DNM2 interaction evidence, BIN1-BACE1 trafficking, and BIN1/tau/clusterin Alzheimer-context interaction evidence. No annotation action changes were needed: BIN1 remains curated primarily as a BAR/SH3 membrane-remodeling and endocytic adaptor, with BACE1/tau/Alzheimer outputs retained as non-core context rather than the defining molecular function.

Falcon deep research integration (2026-06-21)

A Falcon (Edison) deep-research report is now in BIN1-deep-research-falcon.md; it broadly corroborates the existing review's framing of BIN1 as a BAR/SH3 membrane-curvature and endocytic-adaptor protein with non-core muscle T-tubule, cancer/MYC, and Alzheimer roles, adding mechanistic and cardiac detail but no findings that contradict the current annotations. The Falcon-sourced citations below are not yet independently verified against full text.

New or refined findings beyond the existing notes/review:

  • Domain-to-exon architecture mapped explicitly (20 exons): N-BAR exons 1-10, PI domain exon 11, PS linker exon 12, CLAP exons 13-16, MYC-binding domain exons 17-18, SH3 exons 19-20 [Spooner & Dixon, Am J Physiol Heart Circ Physiol 2025, doi:10.1152/ajpheart.00198.2025].
  • Autoinhibition mechanism refined: the PI domain (and exon-13 CLAP segment) binds intramolecularly to the SH3 domain to lock a closed state; PI(4,5)P2 engagement or proline-rich partner binding releases the active open conformation, spatially restricting membrane sculpting [Spooner & Dixon 2025].
  • Quantitative membrane-remodeling detail: tubulation plateaus near ~3% PI(4,5)P2 and depends on cholesterol; Lys164/165/166 in the BAR region anchor acidic phospholipids and their charge-reversal abolishes tubulation [Spooner & Dixon 2025].
  • Cardiac excitation-contraction-coupling role and partners are new vs the existing notes: BIN1 anchors microtubules via the BAR-CLIP-170 interaction to deliver CaV1.2 to T-tubules and scaffolds RyR2 at dyads; BIN1 loss mislocalizes CaV1.2/RyR2 and underlies heart failure [Spooner & Dixon 2025]. (Existing YAML already KEEPs cardiac ISS terms GO:1904878, GO:1903946, GO:0086091, GO:1901380 as non-core; this provides the mechanistic basis.)
  • N-WASP recruited via SH3 to drive ARP2/3 actin polymerization linking T-tubules to cytoskeleton, giving a mechanistic basis for the existing actin-polymerization (GO:0030838) and actin-filament-binding annotations [Spooner & Dixon 2025].
  • MTM1/myotubularin cooperates with BIN1 (favored in the open conformation) to grow elongated muscle tubules, coupling phosphoinositide homeostasis to tubulation [Spooner & Dixon 2025].
  • Alzheimer mechanism refined: legumain cleaves neuronal BIN1 at N277/N288 to produce a BIN1(1-277) fragment found in AD brain that binds tau, accelerates tau aggregation, and promotes transcellular tau spread by enhancing clathrin-mediated endocytosis [Zhang et al., PLOS Biology 2024, doi:10.1371/journal.pbio.3002470]; SH3 binds the tau 216-PTPP-219 proline-rich motif, modulated by tau phosphorylation [Lasorsa et al., Biochemistry 2023, doi:10.1021/acs.biochem.2c00717].
  • AD isoform imbalance refined: shift toward shorter glial isoforms and loss of longer neuronal (CLAP+) isoforms is implicated in pathology [Saha & Karati, Egypt J Med Hum Genet 2025, doi:10.1186/s43042-025-00759-8; Hu et al., bioRxiv 2025, doi:10.1101/2025.03.31.646439].
  • New neuron-specific interactor: RIN2 recruits BIN1 to RAB5-positive early endosomes (neuronal interactome), an AD-relevant endosomal-targeting mechanism [Wei et al., bioRxiv 2026, doi:10.64898/2026.03.14.711835] (0 citations, preprint — treat as preliminary).
  • Centronuclear myopathy genotype-mechanism split reaffirmed: BAR-domain mutations abolish membrane remodeling, whereas SH3 truncations selectively abolish DNM2 recruitment while preserving tubulation [Zambo et al., eLife 2024, doi:10.1101/2023.02.14.528471].

Discrepancies / annotations to revisit:

  • No contradictions with existing annotations were found; the report reinforces the current MODIFY of GO:0019828 (aspartic-type endopeptidase inhibitor activity) toward trafficking terms, since Falcon also frames the BACE1/amyloid effect as trafficking-mediated, not direct protease inhibition.
  • Optional refinement to consider (not required): the BAR-CLIP-170 and SH3-N-WASP/ARP2/3 mechanisms could justify more informative MF terms (e.g. microtubule-anchoring / actin-related), but these are cardiac/muscle-context roles and current non-core framing remains adequate; defer pending full-text verification.

📄 View Raw YAML

 
id: O00499
gene_symbol: BIN1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'BIN1 encodes amphiphysin II, a BAR/N-BAR and SH3-domain membrane-remodeling
  adaptor with extensive alternative splicing in brain and skeletal muscle. BIN1 binds phospholipid
  membranes, senses and generates membrane curvature, promotes lipid tubulation, and organizes
  membrane domains used in endocytosis, synaptic-vesicle cycling, endosomal sorting, and skeletal-muscle
  T-tubule formation. Through SH3-domain interactions with endocytic proteins such as dynamin
  and clathrin/AP2-associated machinery, BIN1 links curved membranes to vesicle trafficking
  and cytoskeletal organization. Additional context-specific functions include nuclear/MYC-related
  tumor-suppressor activities, tau and clusterin interactions, and regulation of BACE1 trafficking
  and amyloid-beta production.'
alternative_products:
- name: IIA
  id: O00499-1
- name: IIB
  id: O00499-2
  sequence_note: VSP_000246, VSP_000252
- name: IIC1
  id: O00499-3
  sequence_note: VSP_000249
- name: IIC2
  id: O00499-4
  sequence_note: VSP_000246, VSP_000249
- name: IID
  id: O00499-5
  sequence_note: VSP_000248
- name: II2
  id: O00499-6
  sequence_note: VSP_000246, VSP_000253
- name: II3
  id: O00499-7
  sequence_note: VSP_000246, VSP_000250
- name: BIN1
  id: O00499-8
  sequence_note: VSP_000246, VSP_000247, VSP_000250
- name: BIN1-10-13
  id: O00499-9
  sequence_note: VSP_000246, VSP_000251
- name: BIN1-13
  id: O00499-10
  sequence_note: VSP_000246, VSP_000247, VSP_000251
- name: BIN1+12A
  id: O00499-11
  sequence_note: VSP_000246, VSP_000247, VSP_000253
existing_annotations:
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0008021
    label: synaptic vesicle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0005543
    label: phospholipid binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: BIN1 BAR/N-BAR domains bind phospholipid membranes and generate or sense 
      membrane curvature.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0048156
    label: tau protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: BIN1-tau interaction is experimentally supported and Alzheimer-relevant, 
      but it is a context-specific disease/pathology interaction rather than the primary
      BAR-domain membrane-remodeling role.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic 
      annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not 
      the main BIN1 membrane-remodeling function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0006897
    label: endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related
      interactions and membrane remodeling.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0030100
    label: regulation of endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related
      interactions and membrane remodeling.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0030315
    label: T-tubule
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: BIN1 is required for muscle membrane organization, especially T-tubule 
      formation and associated sarcomeric membrane domains.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0051649
    label: establishment of localization in cell
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: This process is too broad for BIN1 compared with specific endocytosis, 
      vesicle sorting, and membrane-remodeling terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Use more informative trafficking/endocytosis and membrane-remodeling terms 
      instead of broad establishment of localization in cell.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10903846
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12604805
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12668730
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16275660
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16530520
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18647389
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18985028
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23917616
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24169621
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31413325
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32552912
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23917616
  qualifier: enables
  review:
    summary: This annotation is plausible or supported, but it is more context-specific 
      or less informative than the core BIN1 membrane-remodeling/endocytic functions.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31413325
  qualifier: enables
  review:
    summary: This annotation is plausible or supported, but it is more context-specific 
      or less informative than the core BIN1 membrane-remodeling/endocytic functions.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0008021
    label: synaptic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0030018
    label: Z disc
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: BIN1 is required for muscle membrane organization, especially T-tubule 
      formation and associated sarcomeric membrane domains.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0031674
    label: I band
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: BIN1 is required for muscle membrane organization, especially T-tubule 
      formation and associated sarcomeric membrane domains.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0033268
    label: node of Ranvier
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0043194
    label: axon initial segment
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0043196
    label: varicosity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: This annotation is plausible or supported, but it is more context-specific 
      or less informative than the core BIN1 membrane-remodeling/endocytic functions.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0043679
    label: axon terminus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: This annotation is plausible or supported, but it is more context-specific 
      or less informative than the core BIN1 membrane-remodeling/endocytic functions.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0044300
    label: cerebellar mossy fiber
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: This annotation is plausible or supported, but it is more context-specific 
      or less informative than the core BIN1 membrane-remodeling/endocytic functions.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: This annotation is plausible or supported, but it is more context-specific 
      or less informative than the core BIN1 membrane-remodeling/endocytic functions.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0045807
    label: positive regulation of endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related
      interactions and membrane remodeling.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0048488
    label: synaptic vesicle endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related
      interactions and membrane remodeling.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0051020
    label: GTPase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related
      interactions and membrane remodeling.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0098850
    label: extrinsic component of synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:10412034
  qualifier: involved_in
  review:
    summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic 
      annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not 
      the main BIN1 membrane-remodeling function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:8782822
  qualifier: located_in
  review:
    summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic 
      annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not 
      the main BIN1 membrane-remodeling function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0010564
    label: regulation of cell cycle process
  evidence_type: IDA
  original_reference_id: PMID:8782822
  qualifier: involved_in
  review:
    summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic 
      annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not 
      the main BIN1 membrane-remodeling function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0090571
    label: RNA polymerase II transcription repressor complex
  evidence_type: IPI
  original_reference_id: PMID:15992821
  qualifier: part_of
  review:
    summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic 
      annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not 
      the main BIN1 membrane-remodeling function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:9182667
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005768
    label: endosome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0008289
    label: lipid binding
  evidence_type: EXP
  original_reference_id: PMID:18658220
  qualifier: enables
  review:
    summary: BIN1 BAR/N-BAR domains bind phospholipid membranes and generate or sense 
      membrane curvature.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0060988
    label: lipid tube assembly
  evidence_type: IDA
  original_reference_id: PMID:18658220
  qualifier: involved_in
  review:
    summary: BIN1 has intrinsic membrane-tubulating activity and supports lipid tube or 
      membrane tubule formation.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:1901380
    label: negative regulation of potassium ion transmembrane transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: This annotation is plausible or supported, but it is more context-specific 
      or less informative than the core BIN1 membrane-remodeling/endocytic functions.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:1903946
    label: negative regulation of ventricular cardiac muscle cell action potential
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: This annotation is plausible or supported, but it is more context-specific 
      or less informative than the core BIN1 membrane-remodeling/endocytic functions.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0030838
    label: positive regulation of actin filament polymerization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: This annotation is plausible or supported, but it is more context-specific 
      or less informative than the core BIN1 membrane-remodeling/endocytic functions.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0086091
    label: regulation of heart rate by cardiac conduction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: This annotation is plausible or supported, but it is more context-specific 
      or less informative than the core BIN1 membrane-remodeling/endocytic functions.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:1904878
    label: negative regulation of calcium ion transmembrane transport via high 
      voltage-gated calcium channel
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: This annotation is plausible or supported, but it is more context-specific 
      or less informative than the core BIN1 membrane-remodeling/endocytic functions.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0030424
    label: axon
  evidence_type: ISS
  original_reference_id: PMID:32552912
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: ISS
  original_reference_id: PMID:32552912
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: ISS
  original_reference_id: PMID:32552912
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0019828
    label: aspartic-type endopeptidase inhibitor activity
  evidence_type: IMP
  original_reference_id: PMID:27179792
  qualifier: enables
  review:
    summary: BIN1 regulates BACE1 abundance and amyloid-beta production by endosomal 
      trafficking and lysosomal degradation, not by acting as a direct aspartic protease
      inhibitor.
    action: MODIFY
    proposed_replacement_terms:
    - id: GO:0002020
      label: protease binding
    - id: GO:0008333
      label: endosome to lysosome transport
    - id: GO:1902430
      label: negative regulation of amyloid-beta formation
    reason: Replace direct aspartic-type endopeptidase inhibitor activity with protease 
      binding plus BACE1 trafficking/amyloid-output process terms.
- term:
    id: GO:1902430
    label: negative regulation of amyloid-beta formation
  evidence_type: IMP
  original_reference_id: PMID:27179792
  qualifier: involved_in
  review:
    summary: BIN1 regulation of BACE1 trafficking and amyloid-beta production is 
      supported, but is a cargo-specific Alzheimer-relevant context rather than the core
      BIN1 function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0008333
    label: endosome to lysosome transport
  evidence_type: IMP
  original_reference_id: PMID:27179792
  qualifier: involved_in
  review:
    summary: BIN1 regulation of BACE1 trafficking and amyloid-beta production is 
      supported, but is a cargo-specific Alzheimer-relevant context rather than the core
      BIN1 function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0048156
    label: tau protein binding
  evidence_type: NAS
  original_reference_id: PMID:28386764
  qualifier: enables
  review:
    summary: BIN1-tau interaction is experimentally supported and Alzheimer-relevant, 
      but it is a context-specific disease/pathology interaction rather than the primary
      BAR-domain membrane-remodeling role.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17676042
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0033292
    label: T-tubule organization
  evidence_type: IDA
  original_reference_id: PMID:24755653
  qualifier: involved_in
  review:
    summary: BIN1 is required for muscle membrane organization, especially T-tubule 
      formation and associated sarcomeric membrane domains.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0030315
    label: T-tubule
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: BIN1 is required for muscle membrane organization, especially T-tubule 
      formation and associated sarcomeric membrane domains.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0033292
    label: T-tubule organization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: BIN1 is required for muscle membrane organization, especially T-tubule 
      formation and associated sarcomeric membrane domains.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0002020
    label: protease binding
  evidence_type: IPI
  original_reference_id: PMID:27179792
  qualifier: enables
  review:
    summary: BIN1 regulation of BACE1 trafficking and amyloid-beta production is 
      supported, but is a cargo-specific Alzheimer-relevant context rather than the core
      BIN1 function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:25051234
  qualifier: located_in
  review:
    summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic 
      annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not 
      the main BIN1 membrane-remodeling function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:25051234
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IDA
  original_reference_id: PMID:25051234
  qualifier: colocalizes_with
  review:
    summary: BIN1 couples membrane remodeling to the actin/cytoskeletal system, 
      including direct actin filament binding/remodeling evidence.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0006897
    label: endocytosis
  evidence_type: TAS
  original_reference_id: PMID:23399914
  qualifier: involved_in
  review:
    summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related
      interactions and membrane remodeling.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0006897
    label: endocytosis
  evidence_type: TAS
  original_reference_id: PMID:25051234
  qualifier: involved_in
  review:
    summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related
      interactions and membrane remodeling.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0007010
    label: cytoskeleton organization
  evidence_type: TAS
  original_reference_id: PMID:23399914
  qualifier: involved_in
  review:
    summary: BIN1 couples membrane remodeling to the actin/cytoskeletal system, 
      including direct actin filament binding/remodeling evidence.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:25051234
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:28755476
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0030276
    label: clathrin binding
  evidence_type: TAS
  original_reference_id: PMID:25051234
  qualifier: enables
  review:
    summary: BIN1 functions as an endocytic adaptor through clathrin/AP2/dynamin-related
      interactions and membrane remodeling.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0048156
    label: tau protein binding
  evidence_type: IPI
  original_reference_id: PMID:25051234
  qualifier: enables
  review:
    summary: BIN1-tau interaction is experimentally supported and Alzheimer-relevant, 
      but it is a context-specific disease/pathology interaction rather than the primary
      BAR-domain membrane-remodeling role.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:25051234
  qualifier: enables
  review:
    summary: This annotation is plausible or supported, but it is more context-specific 
      or less informative than the core BIN1 membrane-remodeling/endocytic functions.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867754
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868230
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868236
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868648
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868651
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868658
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868659
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868660
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868661
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8869438
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871193
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871194
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26506308
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0006997
    label: nucleus organization
  evidence_type: IMP
  original_reference_id: PMID:26506308
  qualifier: involved_in
  review:
    summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic 
      annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not 
      the main BIN1 membrane-remodeling function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0051015
    label: actin filament binding
  evidence_type: IDA
  original_reference_id: PMID:26506308
  qualifier: enables
  review:
    summary: BIN1 couples membrane remodeling to the actin/cytoskeletal system, 
      including direct actin filament binding/remodeling evidence.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:16530520
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0043065
    label: positive regulation of apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:16530520
  qualifier: involved_in
  review:
    summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic 
      annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not 
      the main BIN1 membrane-remodeling function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0070063
    label: RNA polymerase binding
  evidence_type: IPI
  original_reference_id: PMID:16530520
  qualifier: enables
  review:
    summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic 
      annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not 
      the main BIN1 membrane-remodeling function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0030018
    label: Z disc
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: BIN1 is required for muscle membrane organization, especially T-tubule 
      formation and associated sarcomeric membrane domains.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0031674
    label: I band
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: BIN1 is required for muscle membrane organization, especially T-tubule 
      formation and associated sarcomeric membrane domains.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0033268
    label: node of Ranvier
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0043194
    label: axon initial segment
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0043065
    label: positive regulation of apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:10412034
  qualifier: involved_in
  review:
    summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic 
      annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not 
      the main BIN1 membrane-remodeling function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0048711
    label: positive regulation of astrocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:10412034
  qualifier: involved_in
  review:
    summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic 
      annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not 
      the main BIN1 membrane-remodeling function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19004523
  qualifier: enables
  review:
    summary: The interaction may be real, but generic protein binding is not an 
      informative molecular-function annotation for BIN1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific BIN1 functions such as phospholipid binding, clathrin 
      binding, GTPase/dynamin binding, actin filament binding, and membrane tubulation.
- term:
    id: GO:0060987
    label: lipid tube
  evidence_type: IMP
  original_reference_id: PMID:19004523
  qualifier: part_of
  review:
    summary: BIN1 has intrinsic membrane-tubulating activity and supports lipid tube or 
      membrane tubule formation.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0060988
    label: lipid tube assembly
  evidence_type: IMP
  original_reference_id: PMID:19004523
  qualifier: involved_in
  review:
    summary: BIN1 has intrinsic membrane-tubulating activity and supports lipid tube or 
      membrane tubule formation.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IDA
  original_reference_id: PMID:23399914
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
- term:
    id: GO:0045664
    label: regulation of neuron differentiation
  evidence_type: IMP
  original_reference_id: PMID:10412034
  qualifier: involved_in
  review:
    summary: This nuclear, transcriptional, cell-cycle, differentiation, or apoptotic 
      annotation reflects tumor-suppressor/isoform-specific or downstream contexts, not 
      the main BIN1 membrane-remodeling function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0048156
    label: tau protein binding
  evidence_type: IPI
  original_reference_id: PMID:23399914
  qualifier: enables
  review:
    summary: BIN1-tau interaction is experimentally supported and Alzheimer-relevant, 
      but it is a context-specific disease/pathology interaction rather than the primary
      BAR-domain membrane-remodeling role.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      represents a context-specific cargo, disease, nuclear/tumor-suppressor, or 
      downstream phenotype rather than BIN1 primary membrane-remodeling function.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: This location or process is consistent with BIN1 membrane-remodeling and 
      endocytic adaptor function in neuronal and muscle contexts.
    action: ACCEPT
    reason: This location is consistent with BIN1 isoform-specific function at cytosolic
      membrane interfaces, endosomes/synaptic vesicles, neuronal axon domains, and 
      skeletal-muscle T-tubules.
- term:
    id: GO:0015629
    label: actin cytoskeleton
  evidence_type: TAS
  original_reference_id: PMID:9182667
  qualifier: located_in
  review:
    summary: BIN1 couples membrane remodeling to the actin/cytoskeletal system, 
      including direct actin filament binding/remodeling evidence.
    action: ACCEPT
    reason: The term aligns with BIN1/amphiphysin II core biology as a BAR-domain and 
      SH3-domain membrane-remodeling adaptor involved in membrane curvature, lipid 
      tubulation, endocytosis, synaptic-vesicle domains, and muscle T-tubule 
      organization.
references:
- id: file:human/BIN1/BIN1-deep-research-falcon.md
  title: Falcon deep research report for BIN1
  findings:
  - statement: Falcon corroborates the review's framing of BIN1 as a modular BAR/SH3
      membrane-remodeling and scaffolding adaptor that couples membrane-curvature
      generation to recruitment of diverse partners across tissue-specific contexts.
    supporting_text: BIN1 functions as a versatile membrane-remodeling and scaffolding
      protein whose modular domain architecture enables integration of membrane
      curvature generation with recruitment of diverse protein partners to execute
      tissue-specific cellular programs.
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to 
    orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location 
    vocabulary mapping, accompanied by conservative changes to GO terms applied by 
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations of 
    expressed fusion proteins in living cells
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to 
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10412034
  title: Induction of apoptosis and differentiation in neuroblastoma and astrocytoma 
    cells by the overexpression of Bin1, a novel Myc interacting protein.
  findings: []
- id: PMID:10903846
  title: Bin2, a functionally nonredundant member of the BAR adaptor gene family.
  findings: []
- id: PMID:12604805
  title: Identification and characterization of amphiphysin II as a novel cellular 
    interaction partner of the hepatitis C virus NS5A protein.
  findings: []
- id: PMID:12668730
  title: Sorting nexin 4 and amphiphysin 2, a new partnership between endocytosis and 
    intracellular trafficking.
  findings: []
- id: PMID:15992821
  title: A structure-based model of the c-Myc/Bin1 protein interaction shows alternative
    splicing of Bin1 and c-Myc phosphorylation are key binding determinants.
  findings: []
- id: PMID:16275660
  title: Identification of VCP/p97, carboxyl terminus of Hsp70-interacting protein 
    (CHIP), and amphiphysin II interaction partners using membrane-based human proteome 
    arrays.
  findings: []
- id: PMID:16530520
  title: The SH3 binding motif of HCV [corrected] NS5A protein interacts with Bin1 and 
    is important for apoptosis and infectivity.
  findings: []
- id: PMID:17676042
  title: Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause 
    autosomal recessive centronuclear myopathy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract supports BIN1 membrane tubulation biology and
      SH3-domain interaction with DNM2/dynamin 2 in muscle membrane remodeling.
- id: PMID:18647389
  title: The central proline rich region of POB1/REPS2 plays a regulatory role in 
    epidermal growth factor receptor endocytosis by binding to 14-3-3 and SH3 
    domain-containing proteins.
  findings: []
- id: PMID:18658220
  title: Structure and dynamics of helix-0 of the N-BAR domain in lipid micelles and 
    bilayers.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract supports N-BAR/BIN1 membrane binding and 
      curvature generation/sensing as the core biochemical function.
- id: PMID:18985028
  title: Hepatitis C virus infection protein network.
  findings: []
- id: PMID:19004523
  title: The membrane-tubulating potential of amphiphysin 2/BIN1 is dependent on the 
    microtubule-binding cytoplasmic linker protein 170 (CLIP-170).
  findings: []
- id: PMID:23399914
  title: Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau 
    pathology.
  findings: []
- id: PMID:23917616
  title: The myotubularin-amphiphysin 2 complex in membrane tubulation and centronuclear
    myopathies.
  findings: []
- id: PMID:24169621
  title: Elucidating novel hepatitis C virus-host interactions using combined mass 
    spectrometry and functional genomics approaches.
  findings: []
- id: PMID:24755653
  title: Mutations in BIN1 associated with centronuclear myopathy disrupt membrane 
    remodeling by affecting protein density and oligomerization.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full-text record supports BIN1 BAR-domain membrane 
      remodeling and disease-mutant disruption of membrane tubulation.
- id: PMID:25051234
  title: Intracellular clusterin interacts with brain isoforms of the bridging 
    integrator 1 and with the microtubule-associated protein Tau in Alzheimer's disease.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached full-text record supports BIN1 interaction with tau 
      and intracellular clusterin in Alzheimer-context brain isoform biology; 
      this is relevant but non-core relative to membrane remodeling.
- id: PMID:26506308
  title: Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by Linking the Nuclear
    Envelope to the Actin and Microtubule Cytoskeleton.
  findings: []
- id: PMID:27179792
  title: BIN1 regulates BACE1 intracellular trafficking and amyloid-β production.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract supports BIN1 regulation of BACE1 
      intracellular trafficking and amyloid-beta production as an 
      Alzheimer-relevant, non-core trafficking output.
- id: PMID:28386764
  title: Roles of tau protein in health and disease.
  findings: []
- id: PMID:28755476
  title: Regulation of the interaction between the neuronal BIN1 isoform 1 and Tau 
    proteins - role of the SH3 domain.
  findings: []
- id: PMID:31413325
  title: HENA, heterogeneous network-based data set for Alzheimer's disease.
  findings: []
- id: PMID:32552912
  title: Upregulation of RIN3 induces endosomal dysfunction in Alzheimer's disease.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human 
    interactome.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:8782822
  title: BIN1 is a novel MYC-interacting protein with features of a tumour suppressor.
  findings: []
- id: PMID:9182667
  title: Amphiphysin II (SH3P9; BIN1), a member of the amphiphysin/Rvs family, is 
    concentrated in the cortical cytomatrix of axon initial segments and nodes of 
    ranvier in brain and around T tubules in skeletal muscle.
  findings: []
- id: Reactome:R-HSA-8867754
  title: F- and N- BAR domain proteins bind the clathrin-coated pit
  findings: []
- id: Reactome:R-HSA-8868230
  title: SNX9 recruits components of the actin polymerizing machinery
  findings: []
- id: Reactome:R-HSA-8868236
  title: BAR domain proteins recruit dynamin
  findings: []
- id: Reactome:R-HSA-8868648
  title: SYNJ hydrolyze PI(4,5)P2 to PI(4)P
  findings: []
- id: Reactome:R-HSA-8868651
  title: Endophilins recruit synaptojanins to the clathrin-coated pit
  findings: []
- id: Reactome:R-HSA-8868658
  title: HSPA8-mediated ATP hydrolysis promotes vesicle uncoating
  findings: []
- id: Reactome:R-HSA-8868659
  title: Clathrin recruits auxilins to the clathrin-coated vesicle
  findings: []
- id: Reactome:R-HSA-8868660
  title: Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle
  findings: []
- id: Reactome:R-HSA-8868661
  title: Dynamin-mediated GTP hydrolysis promotes vesicle scission
  findings: []
- id: Reactome:R-HSA-8869438
  title: Dissociation of clathrin-associated proteins
  findings: []
- id: Reactome:R-HSA-8871193
  title: Dissociation of AAK1 and dephosphorylation of AP-2 mu2
  findings: []
- id: Reactome:R-HSA-8871194
  title: RAB5 and GAPVD1 bind AP-2
  findings: []
core_functions:
- molecular_function:
    id: GO:0005543
    label: phospholipid binding
  description: BIN1 uses its N-BAR/BAR domain to bind phospholipid membranes, sense and 
    generate membrane curvature, and drive membrane tubulation. This membrane-remodeling
    activity underlies T-tubule formation in skeletal muscle and curved membrane 
    intermediates in endocytosis and endosomal trafficking.
  directly_involved_in:
  - id: GO:0060988
    label: lipid tube assembly
  - id: GO:0033292
    label: T-tubule organization
  - id: GO:0006897
    label: endocytosis
  - id: GO:0030100
    label: regulation of endocytosis
  - id: GO:0007010
    label: cytoskeleton organization
  locations:
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0030315
    label: T-tubule
  - id: GO:0005768
    label: endosome
  - id: GO:0016020
    label: membrane
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:18658220
    supporting_text: BAR domains generate and sense membrane curvature
  - reference_id: PMID:18658220
    supporting_text: Deletion of helix-0 reduced tubulation of liposomes by the BAR 
      domain
  - reference_id: PMID:24755653
    supporting_text: two mutants showed impaired membrane tubulation both in vivo and in
      vitro
  - reference_id: PMID:24755653
    supporting_text: BIN1, which contains an N-BAR domain, is assumed to be essential 
      for biogenesis of plasma membrane invaginations (T-tubules) in muscle tissues
  - reference_id: PMID:19004523
    supporting_text: Amphiphysin 2/BIN1 may be an anchoring point on membranes for
      CLIP-170
  - reference_id: file:human/BIN1/BIN1-deep-research-falcon.md
    supporting_text: The BAR domain constitutes the primary determinant of this
      membrane-sculpting capacity, engaging membranes through electrostatic
      interactions and mechanically deforming lipid bilayers into highly curved
      tubular and vesicular structures
- molecular_function:
    id: GO:0051020
    label: GTPase binding
  description: BIN1 acts as an endocytic adaptor through SH3-domain and isoform-specific
    interactions with dynamin and clathrin/AP2-associated machinery, linking curved 
    membrane domains to synaptic-vesicle cycling, endocytosis, and membrane trafficking.
  directly_involved_in:
  - id: GO:0048488
    label: synaptic vesicle endocytosis
  - id: GO:0006897
    label: endocytosis
  - id: GO:0045807
    label: positive regulation of endocytosis
  - id: GO:0033292
    label: T-tubule organization
  locations:
  - id: GO:0008021
    label: synaptic vesicle
  - id: GO:0098850
    label: extrinsic component of synaptic vesicle membrane
  - id: GO:0043194
    label: axon initial segment
  - id: GO:0033268
    label: node of Ranvier
  - id: GO:0030424
    label: axon
  supported_by:
  - reference_id: PMID:17676042
    supporting_text: the functional interaction between BIN1 and DNM2 is necessary for 
      normal muscle function and positioning of nuclei
  - reference_id: PMID:17676042
    supporting_text: a partial truncation of the C-terminal SH3 domain abrogates the 
      interaction with DNM2 and its recruitment to the membrane tubules
  - reference_id: PMID:9182667
    supporting_text: In skeletal muscle, amphiphysin II is concentrated around T 
      tubules, while in brain it is concentrated in the cytomatrix beneath the 
      plasmamembrane of axon initial segments and nodes of Ranvier
  - reference_id: PMID:25051234
    supporting_text: all seven brain-specific BIN1 isoforms have an inserted domain that
      interacts with clathrin and AP2/α-adaptin (CLAP), indicating a key role for 
      neuronal BIN1 in endocytosis
proposed_new_terms: []
suggested_questions:
- question: Which BIN1 isoforms should be treated as functionally distinct for GO 
    curation of neuronal endocytosis, skeletal-muscle T-tubule biogenesis, and 
    nuclear/MYC-associated activities?
  experts:
  - BIN1 isoform experts
  - GO membrane trafficking curators
- question: Should BIN1 regulation of BACE1 abundance be curated as cargo-specific 
    endosomal sorting rather than as direct aspartic protease inhibitor activity?
  experts:
  - APP/BACE1 trafficking experts
  - GO molecular-function curators
suggested_experiments:
- description: Rescue BIN1-null human neurons and myotubes with endogenous-level brain 
    and muscle isoforms, then quantify clathrin/AP2/dynamin recruitment, membrane 
    tubulation, endocytosis, and T-tubule organization.
  hypothesis: BIN1 isoform-specific inserts tune a shared BAR/SH3 membrane-remodeling 
    module toward neuronal endocytosis or skeletal-muscle T-tubule formation.
  experiment_type: endogenous isoform-rescue membrane-remodeling assay
- description: Separate BIN1-BACE1 binding from endosomal sorting by comparing 
    BAR-domain, SH3-domain, and BACE1-binding mutants for BACE1 lysosomal delivery and 
    amyloid-beta production.
  hypothesis: BIN1 reduces amyloid-beta output primarily by BACE1 trafficking and 
    lysosomal degradation rather than direct protease inhibition.
  experiment_type: cargo-specific trafficking separation-of-function assay