BAIAP2L1 (also known as IRTKS, Insulin Receptor Tyrosine Kinase Substrate) is a BAR-superfamily scaffold protein containing an inverse-BAR (I-BAR/IMD) domain that senses and induces negative membrane curvature, an SH3 domain for protein-protein interactions with proline-rich motifs, and a C-terminal actin-binding region. The protein functions as a curvature-sensing adaptor that couples membrane topology with actin cytoskeleton dynamics, promoting filopodium formation and membrane protrusions. IRTKS plays key roles in: (1) plasma membrane shape homeostasis through I-BAR-mediated recognition of nanoscale membrane evaginations and recruitment of Rac1-WAVE-Arp2/3 actin machinery; (2) actin filament bundling through its C-terminal actin-binding region; (3) a nuclear role in heterochromatin maintenance via LLPS condensates with HP1alpha. The protein is exploited by enterohemorrhagic E. coli (EHEC) through its SH3 domain binding to bacterial effector EspF(U) and its IMD domain binding to Tir, enabling pathogen-driven actin pedestal formation.
Definition: A membrane curvature sensing activity mediated by an I-BAR (inverse-BAR) domain that preferentially binds to and induces negative membrane curvature (outward protrusions such as filopodia), in contrast to F-BAR domains that induce positive curvature (invaginations).
Justification: While GO has F-BAR domain binding (GO:1990808), there is no specific term for I-BAR (inverse-BAR) domain activity. I-BAR domains induce negative membrane curvature (outward protrusions) in contrast to F-BAR domains that induce positive curvature (invaginations). This distinction is functionally significant for proteins like IRTKS, IRSp53, and MIM.
Parent term: membrane curvature sensor activity
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cytosol localization is consistent with IRTKS function as a cytoplasmic scaffold protein that can translocate between cytosol and plasma membrane [file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md]. Reason: The cytosolic localization is well-supported by the protein's function as an adaptor that couples cytoskeletal actin dynamics with membrane curvature. IRTKS is recruited from cytosol to membrane sites of actin polymerization. Supporting Evidence: file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md IRTKS localizes to plasma-membrane protrusions/filopodial structures and, unexpectedly, to nuclear puncta/condensates |
| GO:0005654 nucleoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Recent evidence (2024) demonstrates IRTKS undergoes liquid-liquid phase separation and localizes to nuclear puncta/condensates where it contributes to heterochromatin organization through interaction with HP1alpha [file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md]. Reason: The nuclear localization is supported by recent high-quality experimental evidence showing IRTKS forms nuclear condensates essential for heterochromatin stability. This represents a newly characterized function beyond the classical membrane/cytoskeletal role. Supporting Evidence: file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md IRTKS localizes to plasma-membrane protrusions/filopodial structures and, unexpectedly, to nuclear puncta/condensates where it contributes to heterochromatin organization |
| GO:0030838 positive regulation of actin filament polymerization | IBA GO_REF:0000033 | ACCEPT | Summary: IRTKS positively regulates actin polymerization through its SH3 domain-mediated recruitment of actin regulators and through the I-BAR-mediated activation of Rac1-WAVE-Arp2/3 pathway at sites of membrane curvature [file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md]. Reason: This is a core function of IRTKS. The protein promotes actin assembly through multiple mechanisms including SH3-mediated interactions with WASP/N-WASP and recruitment of the Arp2/3 complex machinery. Supporting Evidence: PMID:17430976 Expression of IRTKS induces clusters of short actin bundles rather than filopodia-like protrusions file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md I-BAR proteins (including IRTKS) recognize ~100 nm membrane evaginations after stretch/compression, recruiting Rac1-WAVE/Arp2/3 to polymerize actin |
| GO:0051017 actin filament bundle assembly | IBA GO_REF:0000033 | ACCEPT | Summary: IRTKS induces formation of actin filament bundles through its C-terminal actin-binding region [PMID:17430976]. Reason: This is a core function well-documented by experimental studies. The C-terminal region directly binds F-actin and is required for actin bundle formation. Supporting Evidence: PMID:17430976 Expression of IRTKS induces clusters of short actin bundles rather than filopodia-like protrusions |
| GO:0051764 actin crosslink formation | IBA GO_REF:0000033 | ACCEPT | Summary: IRTKS promotes actin crosslink formation through its actin-bundling activity. This is related to but slightly different from actin bundle assembly. Reason: The actin bundling activity documented in PMID:17430976 involves crosslinking of actin filaments. This is consistent with the broader family function of I-BAR proteins. Supporting Evidence: PMID:17430976 Expression of IRTKS induces clusters of short actin bundles rather than filopodia-like protrusions |
| GO:0003779 actin binding | IEA GO_REF:0000043 | ACCEPT | Summary: IRTKS directly binds F-actin through its C-terminal region. The C-terminal extension interacts with actin filaments [PMID:17430976]. Reason: Direct actin binding is experimentally demonstrated. The C-terminal region is required for actin binding and bundling activity. Supporting Evidence: PMID:17430976 it did interact with actin filaments |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | MODIFY | Summary: IRTKS localizes to the actin cytoskeleton and is a factor known to regulate the cytoskeleton [PMID:19366662]. Reason: While cytoskeleton is accurate, a more specific term exists. IRTKS specifically localizes to the actin cytoskeleton component. Proposed replacements: actin cytoskeleton Supporting Evidence: PMID:19366662 Screening of the mammalian SH3 proteome for the ability to bind EspF(U) identified the SH3 domain of insulin receptor tyrosine kinase substrate (IRTKS), a factor known to regulate the cytoskeleton |
| GO:0007009 plasma membrane organization | IEA GO_REF:0000002 | ACCEPT | Summary: Through its I-BAR domain, IRTKS senses and induces membrane curvature, contributing to plasma membrane shape homeostasis at the nanoscale [file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md]. Reason: This is a core function of IRTKS. The I-BAR domain directly participates in membrane organization by sensing curvature and recruiting actin machinery to restore membrane topology. Supporting Evidence: file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md I-BAR proteins decode nanoscale curvature into localized Arp2/3-mediated actin polymerization to restore membrane topology |
| GO:0030833 regulation of actin filament polymerization | IEA GO_REF:0000002 | MODIFY | Summary: IRTKS regulates actin polymerization through SH3-mediated recruitment of WASP/N-WASP and other actin regulators. Reason: More specific term exists. IRTKS positively regulates actin polymerization rather than general regulation. Proposed replacements: positive regulation of actin filament polymerization Supporting Evidence: PMID:19366662 Screening of the mammalian SH3 proteome for the ability to bind EspF(U) identified the SH3 domain of insulin receptor tyrosine kinase substrate (IRTKS), a factor known to regulate the cytoskeleton |
| GO:0070064 proline-rich region binding | IEA GO_REF:0000117 | ACCEPT | Summary: The IRTKS SH3 domain binds proline-rich motifs (PxxP) in partner proteins including bacterial EspF(U) and mammalian ligands. NMR structure demonstrates tandem PxxP recognition [PMID:21098279]. Reason: This is a core molecular function of the SH3 domain, experimentally validated by NMR structural studies showing high-affinity binding to tandem PxxP motifs. Supporting Evidence: PMID:21098279 Our complex structure reveals a unique type of SH3 interaction based on recognition of tandem PxxP motifs in the ligand |
| GO:0098609 cell-cell adhesion | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: This annotation is inferred from association with adherens junctions and cadherin binding. While IRTKS localizes to adherens junctions, cell-cell adhesion is not its primary function. Reason: IRTKS may participate in cell-cell adhesion contexts through its localization to adherens junctions, but this is not a core function. The primary role is membrane curvature sensing and actin regulation. |
| GO:0005515 protein binding | IPI PMID:21098279 Recognition of tandem PxxP motifs as a unique Src homology 3... | REMOVE | Summary: This paper describes IRTKS SH3 domain binding to EspF(U) via tandem PxxP motifs. This represents proline-rich region binding, not generic protein binding. Reason: GO:0005515 (protein binding) is uninformative. The actual molecular function demonstrated is GO:0070064 (proline-rich region binding) via the SH3 domain, which is already annotated. Supporting Evidence: PMID:21098279 Recognition of tandem PxxP motifs as a unique Src homology 3-binding mode triggers pathogen-driven actin assembly. |
| GO:0005515 protein binding | IPI PMID:22921828 Enterohaemorrhagic Escherichia coli exploits a tryptophan sw... | REMOVE | Summary: This paper demonstrates IRTKS SH3 binding to EspF(U) and N-WASP in a trimolecular complex. The interaction is mediated by the SH3 domain binding proline-rich regions. Reason: GO:0005515 (protein binding) is uninformative. The specific interactions involve SH3 domain-mediated proline-rich region binding (GO:0070064), which captures the molecular mechanism. Supporting Evidence: PMID:22921828 2012 Aug 23. Enterohaemorrhagic Escherichia coli exploits a tryptophan switch to hijack host f-actin assembly. |
| GO:0005515 protein binding | IPI PMID:25519916 The EHEC-host interactome reveals novel targets for the tran... | REMOVE | Summary: This paper identifies BAIAP2L1 as interacting with E. coli TIR in Y2H and LUMIER assays. The IMD domain mediates this interaction. Reason: GO:0005515 (protein binding) is too general. The IMD domain-mediated interaction could be captured by more specific terms related to membrane curvature sensing. Supporting Evidence: PMID:25519916 The EHEC-host interactome reveals novel targets for the translocated intimin receptor. |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | REMOVE | Summary: Large-scale interactome study. Generic protein binding annotation from high-throughput data. Reason: GO:0005515 (protein binding) is uninformative and does not specify the molecular mechanism or binding partner class. Supporting Evidence: PMID:26496610 Oct 22. A human interactome in three quantitative dimensions organized by stoichiometries and abundances. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interactome reference map. High-throughput data without specific mechanistic insight. Reason: GO:0005515 (protein binding) is uninformative for this adapter protein with multiple specific binding activities already characterized. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Dual proteome-scale network study. High-throughput interactome data. Reason: GO:0005515 (protein binding) is uninformative. More specific binding activities (SH3-mediated, actin binding, etc.) are already annotated. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: OpenCell endogenous tagging study. High-throughput localization and interaction data. Reason: GO:0005515 (protein binding) is uninformative and should be replaced by more specific molecular function terms. Supporting Evidence: PMID:35271311 2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: IDA evidence from immunofluorescence data confirms cytosolic localization of IRTKS. Reason: Cytosolic localization is consistent with IRTKS function as a cytoplasmic adaptor that translocates to membrane sites upon activation. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: IRTKS localizes to plasma membrane protrusions through its I-BAR domain which senses membrane curvature [file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md]. Reason: Plasma membrane localization is a core aspect of IRTKS function. The I-BAR domain mediates membrane association at sites of curvature. Supporting Evidence: file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md IRTKS localizes to plasma-membrane protrusions/filopodial structures |
| GO:0032956 regulation of actin cytoskeleton organization | IMP PMID:19366662 Insulin receptor tyrosine kinase substrate links the E. coli... | ACCEPT | Summary: IRTKS regulates actin cytoskeleton organization, demonstrated by genetic depletion blocking pedestal formation during bacterial infection [PMID:19366662]. Reason: This is a core function of IRTKS. Genetic depletion experiments demonstrate its requirement for proper actin cytoskeleton organization during cellular responses. Supporting Evidence: PMID:19366662 Ectopic expression of either the IRTKS SH3 domain or the IMD, or genetic depletion of IRTKS, blocked pedestal formation |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9693125 | ACCEPT | Summary: Reactome pathway annotation for RHOF GTPase cycle indicates cytosolic localization. Reason: Consistent with other cytosol annotations. IRTKS is a cytoplasmic protein recruited to membranes. |
| GO:0005912 adherens junction | HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | KEEP AS NON CORE | Summary: High-throughput proteomic analysis of E-cadherin interactome identified BAIAP2L1 at adherens junctions. Reason: Adherens junction localization is likely secondary to IRTKS's role in linking membrane and actin dynamics. Not a primary localization for core function. Supporting Evidence: PMID:25468996 E-cadherin interactome complexity and robustness resolved by quantitative proteomics. |
| GO:0098641 cadherin binding involved in cell-cell adhesion | HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | KEEP AS NON CORE | Summary: Identified in E-cadherin interactome proteomics study. Reason: While IRTKS may interact in cadherin complexes at adherens junctions, this is not its primary function. The core function is membrane curvature sensing and actin regulation. Supporting Evidence: PMID:25468996 E-cadherin interactome complexity and robustness resolved by quantitative proteomics. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Identified in exosome proteomics from prostatic secretions. Reason: Exosomal presence is likely incidental to IRTKS's cytoplasmic/membrane functions rather than a primary localization. Supporting Evidence: PMID:23533145 2013 Apr 23. In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Identified in urinary exosome proteomics study. Reason: Exosomal detection likely reflects packaging of cytoplasmic proteins into exosomes rather than a specific exosome-associated function. Supporting Evidence: PMID:19056867 2008 Dec 3. Large-scale proteomics and phosphoproteomics of urinary exosomes. |
| GO:0005829 cytosol | IDA PMID:19366662 Insulin receptor tyrosine kinase substrate links the E. coli... | ACCEPT | Summary: IDA evidence for cytosolic localization from bacterial infection study. Reason: Cytosolic localization is well-established and consistent with adapter function. Supporting Evidence: PMID:19366662 translocates 2 effectors that bind to distinct domains of a common host factor to promote the formation of a complex that triggers robust actin assembly at the plasma membrane |
| GO:0015629 actin cytoskeleton | IDA PMID:19366662 Insulin receptor tyrosine kinase substrate links the E. coli... | ACCEPT | Summary: IRTKS localizes to actin cytoskeleton, and triggers robust actin assembly at the plasma membrane [PMID:19366662]. Reason: This is a core localization for IRTKS function in coupling membrane dynamics with actin organization. Supporting Evidence: PMID:19366662 the formation of a complex that triggers robust actin assembly at the plasma membrane |
| GO:0030838 positive regulation of actin filament polymerization | IDA PMID:21098279 Recognition of tandem PxxP motifs as a unique Src homology 3... | ACCEPT | Summary: Structural and functional studies demonstrate IRTKS SH3 domain triggers actin assembly through high-affinity binding to actin regulators [PMID:21098279]. Reason: This is a core function demonstrated by the paper's title emphasizing "pathogen-driven actin assembly" through IRTKS SH3 interactions. Supporting Evidence: PMID:21098279 Recognition of tandem PxxP motifs as a unique Src homology 3-binding mode triggers pathogen-driven actin assembly |
| GO:0070064 proline-rich region binding | IDA PMID:21098279 Recognition of tandem PxxP motifs as a unique Src homology 3... | ACCEPT | Summary: NMR structure of IRTKS SH3 domain demonstrates binding to tandem PxxP motifs with unusually high affinity [PMID:21098279]. Reason: This is a core molecular function of the SH3 domain, validated by structural biology and functional studies. Supporting Evidence: PMID:21098279 EspF(U)-IRTKS interaction is among the highest affinity natural SH3 ligands. Our complex structure reveals a unique type of SH3 interaction based on recognition of tandem PxxP motifs |
| GO:0140090 membrane curvature sensor activity | TAS file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md | NEW | Summary: The I-BAR/IMD domain senses and induces negative membrane curvature, recognizing nanoscale membrane evaginations (~100 nm) generated by mechanical stretch/compression. This curvature sensing triggers recruitment of Rac1-WAVE-Arp2/3 actin machinery to restore membrane topology [file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md]. Reason: This is a core molecular function of IRTKS that is well-documented in recent literature but not present in existing GO annotations. The I-BAR domain defines this protein family's primary function. Supporting Evidence: file:human/BAIAP2L1/BAIAP2L1-deep-research-falcon.md I-BAR proteins decode nanoscale curvature into localized Arp2/3-mediated actin polymerization to restore membrane topology |
| GO:0035591 signaling adaptor activity | IDA PMID:19366662 Insulin receptor tyrosine kinase substrate links the E. coli... | NEW | Summary: IRTKS functions as a signaling adaptor bridging membrane curvature sensing (IMD domain), actin regulators (SH3 domain), and F-actin (C-terminal region). It links multiple effectors to coordinate membrane and cytoskeleton dynamics [PMID:19366662]. Reason: IRTKS has been demonstrated to function as an adaptor linking distinct domains to coordinate signaling between membrane and actin dynamics. This adaptor function is central to its role in both normal physiology and pathogen exploitation. Supporting Evidence: PMID:19366662 translocates 2 effectors that bind to distinct domains of a common host factor to promote the formation of a complex that triggers robust actin assembly |
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Download this section (compressed HTML)Q: What is the relative contribution of IRTKS to heterochromatin maintenance versus membrane/cytoskeleton dynamics in different cell types?
Q: Are there specific endogenous ligands for the IRTKS SH3 domain that compete with bacterial effectors during infection?
Experiment: Live-cell imaging with IRTKS biosensors to track dynamic translocation between cytosol, membrane protrusions, and nuclear condensates. Understanding the kinetics and triggers for IRTKS localization changes would clarify how cells coordinate its multiple functions.
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