BAIAP2L2 (Pinkbar) is an epithelial-specific I-BAR domain-containing adapter protein that generates planar membrane structures rather than tubular protrusions typical of other I-BAR family members. The protein contains an N-terminal I-BAR/IMD domain (aa 1-239) with a relatively flat lipid-binding interface and a C-terminal SH3 domain (aa 324-387). Unlike IRSp53 which induces membrane tubulation, Pinkbar promotes the formation of planar membrane sheets through its unique oligomerization properties. The protein binds phosphoinositides including PtdIns(4,5)P2 and localizes to RAB13-positive vesicles and plasma membrane at intercellular junctions in intestinal epithelial cells. In hair cells, BAIAP2L2 localizes to stereocilia tips in a Ca2+-dependent manner via a tripartite complex with MYO15A and EPS8, playing a role in stereocilia maintenance and mechanotransduction.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation based on phylogenetic inference from PANTHER family analysis. While BAIAP2L2 may have some cytosolic pool before membrane recruitment, the primary functional localization is at plasma membrane, vesicle membranes, and cell junctions. This is a non-specific localization that does not capture the functionally relevant sites. Reason: The cytosolic localization is likely a general feature inherited from the IRSp53 family (which includes BAIAP2, BAIAP2L1) but does not reflect the primary functional localization of Pinkbar. The key experimental localizations are membrane-associated: RAB13-positive vesicles, plasma membrane at intercellular contacts [PMID:21743456], and stereocilia tips in hair cells. Keep as non-core since cytosolic pool exists before membrane recruitment. Supporting Evidence: PMID:21743456 We show that a previously uncharacterized member of the I-BAR subfamily, Pinkbar, is specifically expressed in intestinal epithelial cells, where it localizes to Rab13-positive vesicles and to the plasma membrane at intercellular junctions. |
| GO:0005654 nucleoplasm | IBA GO_REF:0000033 | UNDECIDED | Summary: Nucleoplasmic localization of BAIAP2L2 remains unresolved. Reason: The historical GOA nucleus-related assignment is IBA from PTN001022094, not an unidentified model prediction. The current PTHR14206 PAINT snapshot omits the nucleoplasm row, and the focused OpenScientist report independently finds no current nuclear GO/HPA call. Direct studies establish epithelial membrane/vesicle and cochlear stereocilia-tip localization. Nevertheless, those positive localizations do not establish exclusivity; missing HPA data and a simple classical-NLS scan do not exclude a context-dependent pool or nonclassical import. The report itself states these limitations. Retain UNDECIDED because the old assertion has a version/provenance discrepancy and no direct target-specific localization-loss evidence was recovered. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN001022094 · PTN001022094 UNRESOLVED The old GOA snapshot gives PTN001022094; the current family PAINT export and focused research lack this nucleoplasm row. The version discrepancy is confirmed, but primary membrane localization and absent predicted NLS do not establish a biological loss. Supporting Evidence: file:human/BAIAP2L2/BAIAP2L2-hypotheses/kgap-baiap2l2-epithelial-pinkbar-function/openscientist.md Native epithelial function = "unresolved." PMID:21743456 We show that a previously uncharacterized member of the I-BAR subfamily, Pinkbar, is specifically expressed in intestinal epithelial cells, where it localizes to Rab13-positive vesicles and to the plasma membrane at intercellular junctions. file:human/BAIAP2L2/BAIAP2L2-hypotheses/function-hypothesis-go-0005654/openscientist.md Absence of a classical NLS does not exclude non-classical or piggyback import |
| GO:0030838 positive regulation of actin filament polymerization | IBA GO_REF:0000033 | UNDECIDED | Summary: IBA annotation inferred from phylogeny with other I-BAR family members like IRSp53. While IRSp53 directly promotes actin polymerization through effector interactions, Pinkbar's role appears more focused on membrane organization and planar structure generation rather than direct actin regulation. Reason: The PAINT assertion at PTN001022094 requires assessment of conserved actin-regulatory function in this descendant. Scaffolding actin regulators can constitute participation, so lack of intrinsic actin catalysis is not a sufficient objection. The existing OpenScientist assessment supports distinct membrane-shaping and cochlear-scaffolding roles and warns that a normal basal epithelial knockout phenotype does not exclude redundancy or challenge-dependent function. It does not resolve this specific actin-polymerization/bundling/crosslinking claim. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN001022094 · PTN001022094 UNRESOLVED Conservation of this particular actin-regulatory assertion remains uncertain; neither planar membrane geometry nor absence of a basal single-knockout phenotype proves loss. Supporting Evidence: file:human/BAIAP2L2/BAIAP2L2-hypotheses/kgap-baiap2l2-epithelial-pinkbar-function/openscientist.md BAIAP2L2 maintains **cochlear stereocilia** PMID:21743456 Notably, the BAR domain of Pinkbar does not induce membrane tubulation but promotes the formation of planar membrane sheets. |
| GO:0051017 actin filament bundle assembly | IBA GO_REF:0000033 | UNDECIDED | Summary: IBA annotation based on phylogenetic relationship to other I-BAR family members. IRSp53 family proteins are known to be involved in actin bundling. For BAIAP2L2 specifically, the stereocilia localization suggests involvement in actin-based structures but direct experimental evidence for bundle assembly activity is limited. Reason: The PAINT assertion at PTN001022094 requires assessment of conserved actin-regulatory function in this descendant. Scaffolding actin regulators can constitute participation, so lack of intrinsic actin catalysis is not a sufficient objection. The existing OpenScientist assessment supports distinct membrane-shaping and cochlear-scaffolding roles and warns that a normal basal epithelial knockout phenotype does not exclude redundancy or challenge-dependent function. It does not resolve this specific actin-polymerization/bundling/crosslinking claim. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN001022094 · PTN001022094 UNRESOLVED Conservation of this particular actin-regulatory assertion remains uncertain; neither planar membrane geometry nor absence of a basal single-knockout phenotype proves loss. Supporting Evidence: file:human/BAIAP2L2/BAIAP2L2-hypotheses/kgap-baiap2l2-epithelial-pinkbar-function/openscientist.md BAIAP2L2 maintains **cochlear stereocilia** |
| GO:0051764 actin crosslink formation | IBA GO_REF:0000033 | UNDECIDED | Summary: IBA annotation inferred from phylogeny with IRSp53 family. No direct experimental evidence for BAIAP2L2/Pinkbar having actin crosslinking activity. Reason: The PAINT assertion at PTN001022094 requires assessment of conserved actin-regulatory function in this descendant. Scaffolding actin regulators can constitute participation, so lack of intrinsic actin catalysis is not a sufficient objection. The existing OpenScientist assessment supports distinct membrane-shaping and cochlear-scaffolding roles and warns that a normal basal epithelial knockout phenotype does not exclude redundancy or challenge-dependent function. It does not resolve this specific actin-polymerization/bundling/crosslinking claim. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN001022094 · PTN001022094 UNRESOLVED Conservation of this particular actin-regulatory assertion remains uncertain; neither planar membrane geometry nor absence of a basal single-knockout phenotype proves loss. Supporting Evidence: file:human/BAIAP2L2/BAIAP2L2-hypotheses/kgap-baiap2l2-epithelial-pinkbar-function/openscientist.md BAIAP2L2 maintains **cochlear stereocilia** |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location. Well-supported by experimental evidence showing plasma membrane localization at intercellular contacts in epithelial cells and at stereocilia tips in hair cells. Reason: Plasma membrane localization is experimentally validated. PMID:21743456 shows Pinkbar localizes to the plasma membrane at intercellular junctions. The I-BAR domain binds phosphoinositides in the plasma membrane inner leaflet. Supporting Evidence: PMID:21743456 We show that a previously uncharacterized member of the I-BAR subfamily, Pinkbar, is specifically expressed in intestinal epithelial cells, where it localizes to Rab13-positive vesicles and to the plasma membrane at intercellular junctions. |
| GO:0007009 plasma membrane organization | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro I-BAR domain mapping. This is well-supported by experimental evidence that Pinkbar generates planar membrane structures at the plasma membrane. Reason: BAIAP2L2/Pinkbar is directly involved in organizing plasma membrane structure through its unique I-BAR domain that generates planar membrane sheets rather than tubules [PMID:21743456]. This is a core function of the protein. Supporting Evidence: PMID:21743456 Notably, the BAR domain of Pinkbar does not induce membrane tubulation but promotes the formation of planar membrane sheets. |
| GO:0008289 lipid binding | IEA GO_REF:0000043 | MODIFY | Summary: IEA annotation from UniProt keyword mapping. While technically correct, this term is too general. The protein specifically binds phosphoinositides. Reason: Lipid binding is too general. BAIAP2L2 specifically binds phosphoinositides including PtdIns(4,5)P2 through its I-BAR domain [PMID:21743456, UniProt]. A more specific term should be used. Proposed replacements: phosphatidylinositol-4,5-bisphosphate binding |
| GO:0030659 cytoplasmic vesicle membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation from UniProt subcellular location. Supported by experimental evidence showing localization to RAB13-positive vesicle membranes. Reason: Experimentally validated. PMID:21743456 demonstrates that Pinkbar localizes to RAB13-positive vesicles in epithelial cells. Supporting Evidence: PMID:21743456 We show that a previously uncharacterized member of the I-BAR subfamily, Pinkbar, is specifically expressed in intestinal epithelial cells, where it localizes to Rab13-positive vesicles and to the plasma membrane at intercellular junctions. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation from UniProt keyword mapping. Supported by evidence for RAB13-positive vesicle localization, though the more specific vesicle membrane term is preferred. Reason: Localization to cytoplasmic vesicles (specifically RAB13-positive vesicles) is experimentally demonstrated [PMID:21743456]. This is consistent with the vesicle membrane annotation and represents a valid localization. Supporting Evidence: PMID:21743456 We show that a previously uncharacterized member of the I-BAR subfamily, Pinkbar, is specifically expressed in intestinal epithelial cells, where it localizes to Rab13-positive vesicles and to the plasma membrane at intercellular junctions. |
| GO:0070161 anchoring junction | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation from UniProt subcellular location. The cell junction localization is experimentally supported, though "anchoring junction" is somewhat specific. Reason: BAIAP2L2 localizes to cell junctions in epithelial cells [PMID:21743456]. Intercellular contacts where Pinkbar localizes include anchoring junction structures in epithelial tissue. Supporting Evidence: PMID:21743456 We show that a previously uncharacterized member of the I-BAR subfamily, Pinkbar, is specifically expressed in intestinal epithelial cells, where it localizes to Rab13-positive vesicles and to the plasma membrane at intercellular junctions. |
| GO:0005543 phospholipid binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara orthology to mouse Q80Y61. Supported by experimental evidence for phosphoinositide binding, though more specific terms exist. Reason: Phospholipid binding through the I-BAR domain is well-established for this protein family. UniProt states BAIAP2L2 binds phosphoinositides including PtdIns(4,5)P2. While more specific phosphoinositide binding terms would be better, this general term is acceptable. Supporting Evidence: PMID:21743456 Structural and mutagenesis analyses reveal that the BAR domain of Pinkbar has a relatively flat lipid-binding interface and that it assembles into sheet-like oligomers in crystals and in solution |
| GO:0061024 membrane organization | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara orthology. This is a core function of BAIAP2L2 - organizing membrane structure by generating planar membrane sheets. Reason: Membrane organization is a core molecular function of BAIAP2L2. The protein generates planar membrane structures through its unique I-BAR domain [PMID:21743456]. This is well-supported experimentally. Supporting Evidence: PMID:21743456 Notably, the BAR domain of Pinkbar does not induce membrane tubulation but promotes the formation of planar membrane sheets. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9693125 | KEEP AS NON CORE | Summary: TAS annotation from Reactome pathway "RHOF binds effectors at the plasma membrane". Duplicate of IBA annotation above. Cytosolic pool exists as part of dynamic membrane recruitment. Reason: Cytosolic localization represents the pool of BAIAP2L2 before membrane recruitment. The Reactome pathway describes RHOF-mediated recruitment of effectors to plasma membrane, suggesting BAIAP2L2 cycles between cytosol and membrane. Keep as non-core since the primary function is at membrane. |
| GO:0071439 clathrin complex | IDA PMID:21401524 Functional analysis of Dictyostelium IBARa reveals a conserv... | ACCEPT | Summary: IDA annotation from direct assay showing human BAIAP2L2 co-localizes with clathrin plaques, supporting a role in clathrin-mediated endocytosis. This is primary experimental evidence for a conserved role in endocytosis. Reason: PMID:21401524 directly demonstrates that human BAIAP2L2 co-localizes tightly with clathrin plaques, supporting a role in generating membrane curvature for clathrin-mediated endocytosis. This represents a conserved function of I-BAR proteins in vesicle trafficking. Supporting Evidence: PMID:21401524 human BAIAP2L2 (brain-specific angiogenesis inhibitor 1-associated protein 2-like 2) also tightly co-localizes with clathrin plaques |
| GO:0005543 phospholipid binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation based on sequence similarity to mouse ortholog Q80Y61. Duplicate of IEA annotation above. Supported by I-BAR domain-mediated lipid binding. Reason: Phospholipid binding is a core molecular function mediated by the I-BAR domain. The ISS evidence from mouse ortholog is valid given high sequence conservation of the I-BAR domain. |
| GO:0012506 vesicle membrane | IDA PMID:21743456 Pinkbar is an epithelial-specific BAR domain protein that ge... | ACCEPT | Summary: IDA annotation from direct experimental evidence showing localization to vesicle membranes in epithelial cells. This is primary experimental data. Reason: PMID:21743456 directly demonstrates localization to RAB13-positive vesicle membranes in intestinal epithelial cells. This is well-validated experimental evidence for a key localization. Supporting Evidence: PMID:21743456 We show that a previously uncharacterized member of the I-BAR subfamily, Pinkbar, is specifically expressed in intestinal epithelial cells, where it localizes to Rab13-positive vesicles and to the plasma membrane at intercellular junctions. |
| GO:0044291 cell-cell contact zone | IDA PMID:21743456 Pinkbar is an epithelial-specific BAR domain protein that ge... | ACCEPT | Summary: IDA annotation from direct experimental evidence showing localization at intercellular contacts in epithelial cells. Reason: PMID:21743456 directly shows Pinkbar localizes to the plasma membrane at intercellular junctions in epithelial cells. This is core localization data. Supporting Evidence: PMID:21743456 We show that a previously uncharacterized member of the I-BAR subfamily, Pinkbar, is specifically expressed in intestinal epithelial cells, where it localizes to Rab13-positive vesicles and to the plasma membrane at intercellular junctions. |
| GO:0061024 membrane organization | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation based on sequence similarity to mouse ortholog. Duplicate of IEA annotation above. Well-supported as a core function. Reason: Membrane organization is a core function supported by experimental evidence showing Pinkbar generates planar membrane structures [PMID:21743456]. |
| GO:0032426 stereocilium tip | IDA DOI:10.1091/mbc.e21-10-0491 | NEW | Summary: Halford et al. 2022 demonstrates Ca2+-dependent localization of BAIAP2L2 to stereocilia tips in hair cells, where it is retained via mechanotransduction channel activity. Evidence from deep research review. Reason: Experimental evidence from Halford et al. 2022 (Mol Biol Cell) shows BAIAP2L2 localizes to stereocilia tips in a Ca2+-dependent manner. This localization requires functional mechanotransduction channels and is mediated by the MYO15A-EPS8-BAIAP2L2 complex. Supporting Evidence: file:human/BAIAP2L2/BAIAP2L2-deep-research-falcon.md BAIAP2L2 becomes highly enriched at the tips of stereocilia (with row-specific enrichment) in cochlear hair cells. Tip localization requires functional mechanotransduction (MET) channels and is lost upon acute pharmacological channel block or intracellular Ca2+ chelation |
| GO:0097753 membrane bending | IDA PMID:21743456 Pinkbar is an epithelial-specific BAR domain protein that ge... | NEW | Summary: Pinkbar's I-BAR domain generates planar membrane structures, a specialized form of membrane deformation distinct from tubulation. Reason: PMID:21743456 demonstrates that Pinkbar's BAR domain promotes formation of planar membrane sheets through its flat lipid-binding interface and sheet-like oligomers. This represents a form of membrane bending/organization activity. Supporting Evidence: PMID:21743456 Notably, the BAR domain of Pinkbar does not induce membrane tubulation but promotes the formation of planar membrane sheets. |
| GO:0120045 stereocilium maintenance | IMP DOI:10.1091/mbc.e21-10-0491 | NEW | Summary: Loss of Baiap2l2 destabilizes transducing stereocilia and leads to deafness in mouse models, indicating a role in stereocilia maintenance. Evidence from deep research review. Reason: Halford et al. 2022 cites prior work showing that loss of Baiap2l2 destabilizes transducing stereocilia and causes deafness, indicating the protein functions in maintaining stereocilia structure and mechanotransduction apparatus. Supporting Evidence: file:human/BAIAP2L2/BAIAP2L2-deep-research-falcon.md Prior work summarized by Halford et al. indicates that loss of Baiap2l2 destabilizes transducing stereocilia and leads to deafness, linking BAIAP2L2 to maintenance of the mechanotransduction apparatus and auditory function |
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Download this section (compressed HTML)Q: Does BAIAP2L2 directly regulate actin dynamics through its SH3 domain interactions, or is its role primarily in membrane organization with indirect effects on actin?
Q: What is the functional significance of the oncogenic roles reported in HCC and other cancers - is this related to normal membrane/cytoskeletal functions or represents gain-of-function?
Q: What are the specific phosphoinositide binding preferences of Pinkbar's I-BAR domain compared to other family members?
Experiment: Liposome tubulation/deformation assays with purified BAIAP2L2 I-BAR domain to directly characterize membrane shaping activity and confirm planar structure generation
Experiment: SH3 domain interactome characterization to identify actin regulatory binding partners in epithelial cells
Experiment: Cryo-EM of BAIAP2L2-membrane complexes to visualize the planar oligomeric arrangement predicted from crystal structures
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