BAIAP2

BAR/IMD domain containing adaptor protein 2

2 disorders 1 no genetic record 1 causative 17q25.3 gene with protein product

HGNC:947 Monarch NCBI Gene 10458 ENSG00000175866 UniProt Q9UQB8 OMIM 605475

Aliases: BAP2, IRSp53, WAML.

Normal function · from ai-gene-review (Q9UQB8, commit 79fe13b38970) · AI-generated, not KB evidence

BAR/IMD domain-containing adapter protein 2 (IRSp53) is a curvature-sensitive membrane-cytoskeleton adaptor that couples plasma membrane shape to actin remodeling. The protein contains an N-terminal I-BAR/IMD domain that senses and generates negative membrane curvature by binding PI(4,5)P2-rich membranes, a central CRIB/proline-rich region for small GTPase (Rac1/Cdc42) coupling, and a C-terminal SH3 domain that recruits actin nucleation-promoting factors (WAVE, N-WASP, Eps8, Mena/VASP). IRSp53 integrates Rho-family GTPase signaling with actin network assembly to drive filopodia, lamellipodia, and membrane ruffles, and is held in an autoinhibited conformation by 14-3-3 binding to a phosphorylated region between the CRIB and SH3 modules. The protein is enriched at plasma membrane protrusions and at sites of negative membrane curvature, where it couples membrane shape to a Rac1/Arp2/3 actin burst that restores the membrane's resting topography. In neurons it is a postsynaptic density protein that binds PSD-95, PSD-93 and the Shank scaffolds and drives dendritic spine morphogenesis; loss of function disrupts cortical neuronal migration, and variants that break the autoinhibited state cause developmental and epileptic encephalopathy.

IRSp53 is fundamentally an adaptor that bridges the plasma membrane and the Rho-family GTPases to the actin machinery. The central partial-CRIB and proline-rich region receives activated Cdc42 and Rac1; the C-terminal SH3 domain recruits the actin effectors that do the polymerizing and bundling -- WAVE2, N-WASP, Eps8 and Mena/VASP. IRSp53 itself neither nucleates nor elongates filaments; its contribution is to hold the GTPase signal, the membrane surface and the nucleation-promoting factor in the same place, which is what determines whether a protrusion forms and what shape it takes. The same adaptor logic operates in neurons, where binding to PSD-95/PSD-93 and the Shank family positions IRSp53 in the postsynaptic density and drives dendritic spine morphogenesis.

molecular function: protein-macromolecule adaptor activity · directly involved in: filopodium assembly; regulation of actin cytoskeleton organization; positive regulation of dendritic spine morphogenesis · locations: plasma membrane; postsynaptic density

The N-terminal I-BAR/IMD domain reads negative membrane curvature, and this is what makes IRSp53 a shape sensor rather than a constitutive scaffold. Quiroga et al. compressed fibroblasts to generate bud-shaped plasma membrane evaginations on the ~100 nm scale and found IRSp53 selectively enriched at them, with maximal sorting near 0.05 nm^-1 and roughly twofold enrichment over control. Enrichment creates a local node that couples membrane topography to a transient Rac1/Arp2/3 actin burst, which re-flattens the evagination -- a mechanochemical feedback loop maintaining plasma membrane shape homeostasis.

molecular function: membrane curvature sensor activity · directly involved in: plasma membrane organization · locations: plasma membrane

Direct binding of the IMD/I-BAR domain to PI(4,5)P2 is the membrane-targeting step on which the adaptor and curvature-sensing activities both depend, and it is the feature that distinguishes the I-BAR subfamily mechanically. Mattila et al. mapped the PI(4,5)P2-binding site and showed that its geometry is inverted relative to classical BAR domains, so the domain binds the interior of the tubule and induces curvature of the opposite sign; this is the molecular reason I-BAR proteins generate plasma membrane protrusions where BAR proteins generate invaginations. The same study found the filopodia-forming activity of the IMD to depend on this membrane-deforming activity rather than on the previously proposed F-actin-bundling or GTPase-binding activities -- a point worth carrying, since it means the actin bundling terms this gene carries by IBA are a secondary property of the domain and not the mechanism by which it builds protrusions.

molecular function: phosphatidylinositol-4,5-bisphosphate binding · directly involved in: filopodium assembly · locations: plasma membrane

The IMD binds F-actin directly and cross-links filaments into tightly packed parallel bundles, an activity mapped to conserved basic residues at the two extreme ends of the zeppelin-shaped dimer. This is the molecular function underlying the actin filament bundle assembly and actin crosslink formation processes the gene is annotated to, and it had no molecular-function representation in GOA. It is listed last deliberately: Mattila et al. showed the filopodia-forming activity of the domain survives loss of F-actin bundling and tracks membrane deformation instead, so actin binding is a genuine property of the domain rather than the mechanism by which protrusions are built. In cells it operates alongside Eps8, with which IRSp53 synergizes to bundle actin.

molecular function: actin binding · directly involved in: actin filament bundle assembly; actin crosslink formation · locations: plasma membrane

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Genetic Developmental and Epileptic Encephalopathy	causative	mechanism: Genetic Lesion in an Ion Channel or Synaptic Gene subtype: DEE120 scoped to subtype: DEE120
Alzheimer Disease	no genetic record	mechanism: Intercellular Tau Transmission via Extracellular Vesicles

Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.