{"uniprot":"Q8N944","gene":"AMER3","name":"APC membrane recruitment protein 3","organism":"Homo sapiens (Human)","status":"dark","length":861,"sequence":"MELKRGKTFIKSSLQVSHEKPPDPAAVAAAREGTGPWSVLPGGQQRPHSEKGPQASPSAQEYDRCPNKGAQLDPKGGPAALCGATFKPVRKCKTHDSMSGAGRATAATGQLVGSASFPGSPGSRRMIDYRHFVPQMPFVPAVAKSIPRKRISLKRPKKCFRNLFHIRRNKTEDLASLAAEGKSLPSPGDPSDPGGRRSKAFLPPGEGPGLDGLCQDLLDSELLADASFGLCRALCEDVASLQSFDSLTGCGEVFADESSVPSLELNEGPESPTQAAQGLESKVPRGPLQGSVEQLASPAQNEASDFTRFWDSVNRSVRQQQRALLGPWLSGPQGTDRDQSRLDTAGLAELPLCPCRDPRSGSKASSIDTGTPKSEQPESVSTSDEGYYDSFSPGLEEDKKEAESPGTPAATFPRDSYSGDALYELFHDPSEGPLGPSPDDDLCVSESLSGPALGTPLSICSFRVGAEENLAPAPGPDLLSQGFLQSSWKGKECLLKLCDTELAITMGIVSWLRRGPTPRAPPTPGQPAAPPGSQGAPRAPTEKLGGREGLASDAGGATVCSAPSRQELWAHPGTTGLLAGESKALGGATQGTGTLSRDASREEETRGHSEGLFSSMESAATSTTDTSGKNKAPVPSTWPCSQKEPGPPGVLGCFRGPWRPGHGGDTLDAEPMLAGCVARVAALKISSNEQPPAAWPPRQDMGSGLFGQRWARGPDMLEQKQSSSSPSMTTIHGLPYSASTQDQRCRDRVQDLSWLRVEPTGLGVQAWASVEDQPLQLSTEAVEQVAHGSQLDSEPRSAPAARWSSQGHHPESLGLTLNSQQEGGVSASAPECRCSLLAREGLLCGQPEVGASGPAMAEPHL","function_summary":"A cytosolic adaptor that transiently associates with membranes to assemble signaling complexes that restrain beta-catenin activity. By scaffolding partners that promote beta-catenin turnover, it dampens canonical Wnt pathway output, a control point essential for brain development and for maintaining cochlear hair cell viability and hearing. The protein cycles between a soluble pool and membrane-proximal assemblies, using multivalent binding surfaces to recruit and organize the machinery that enforces pathway repression.","plain_language":"AMER3 has barely been studied. The model's best guess: A cytosolic adaptor that transiently associates with membranes to assemble signaling complexes that restrain beta-catenin activity. By scaffolding partners that promote beta-catenin turnover, it dampens canonical Wnt pathway output, a control point essential for brain development and for maintaining cochlear hair cell viability and hearing.","uniprot_summary":"Negatively regulates the canonical Wnt signaling pathway. Involved in brain development and hearing (By similarity).","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0090090","label":"negative regulation of canonical Wnt signaling pathway"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0005886","label":"plasma membrane"}]},"interpro":[{"id":"IPR019003","name":"APC membrane recruitment protein","type":"family","start":1,"end":739}],"reasoning":"I begin with the InterPro architecture: IPR019003 (APC membrane recruitment protein family) spans residues 1–739, covering essentially the entire polypeptide. A full-length family signature of this kind indicates a dedicated scaffold/adaptor specialized for membrane-associated signaling. Members of this family are characterized by high-capacity protein–protein interaction surfaces that recruit membranes and cytosolic complexes. This architecture causes a primary molecular function of multivalent protein binding, aligning with GO:0005515 protein binding.\n\nA membrane-recruitment scaffold of this family is classically wired into the beta-catenin destruction logic of the Wnt pathway. By assembling and positioning partners that target beta-catenin for turnover, such scaffolds attenuate pathway output. This causal role—organizing effectors that reduce beta-catenin stability—maps directly to GO:0090090 negative regulation of canonical Wnt signaling pathway. The same scaffold logic explains developmental and tissue-level outcomes: dampening Wnt signaling is a prerequisite for proper neurogenesis and for maintaining cochlear hair cell viability; thus, the architecture supports roles in brain development and hearing.\n\nCellular localization follows from the scaffold’s dual life cycle. The absence of transmembrane segments and the presence of a membrane-recruitment family signature predict a soluble pool that transiently associates with membranes through partner binding. This yields a cytosolic reservoir (GO:0005829 cytosol) and a membrane-engaged fraction at the cell surface or endocytic intermediates (GO:0005886 plasma membrane). The experimentally observed cytoplasmic and peripheral membrane behavior is therefore a direct consequence of this adaptor architecture.\n\nMechanistically, the protein likely operates as a membrane-tethered hub that nucleates complexes controlling beta-catenin availability. By concentrating the destruction machinery near membranes—where receptor-proximal Wnt signals converge—it can bias beta-catenin toward degradation, thereby restraining transcriptional outputs. From this, I hypothesize interactions with core Wnt-suppressive modules and membrane-proximal adaptors. Candidate partners include the beta-catenin pathway scaffold and its effectors (APC, AXIN1/AXIN2, GSK3B, CSNK1A1), membrane-associated adaptors that couple to receptor tails (DVL proteins), and endocytic/clathrin adaptors that stabilize membrane association. Together, these assemblies explain how a cytosolic/peripheral membrane scaffold enforces negative regulation of canonical Wnt signaling and supports neurodevelopmental and auditory cell-fate programs.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q8N944.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q8N944"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q8N944/entry","atlas":"/p/Q8N944"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}