{"uniprot":"Q9Y5G5","gene":"PCDHGA8","name":"Protocadherin gamma-A8","organism":"Homo sapiens (Human)","status":"dark","length":932,"sequence":"MAAPQSRPRRGELILLCALLGTLWEIGRGQIRYSVPEETDKGSFVGNISKDLGLDPRKLAKHGVRIVSRGRTQLFALNPRSGSLITAGRIDREELCAQSPRCLININTLVEDKGKLFGVEIEIIDINDNNPKFQVEDLEVKINEIAVPGARYPLPEAVDPDVGVNSLQSYQLSPNHHFSLDVQTGDNGAINPELVLERALDREEEAAHHLVLTASDGGKPPRSSTVRIHVTVLDTNDNAPVFPHPIYRVKVLENMPPGTRLLTVTASDPDEGINGKVAYKFRKINEKQTPLFQLNENTGEISIAKSLDYEECSFYEMEIQAEDVGALLGRTKLLISVEDVNDNRPEVIITSLFSPVLENSLPGTVIAFLSVHDQDSGKNGQVVCYTRDNLPFKLEKSIGNYYRLVTRKYLDRENVSIYNITVMASDLGTPPLSTETQIALHVADINDNPPTFPHASYSAYILENNLRGASIFSLTAHDPDSQENAQVTYSVTEDTLQGAPLSSYISINSDTGVLYALQSFDYEQIRDLQLLVTASDSGDPPLSSNMSLSLFVLDQNDNAPEILYPALPTDGSTGVELAPRSAERGYLVTKVVAVDRDSGQNAWLSYRLLKASEPGLFSVGLHTGEVRTARALLDRDALKQSLVVAVQDHGQPPLSATVTLTVAVADSIPEVLTELGSLKPSVDPNDSSLTLYLVVAVAAISCVFLAFVAVLLGLRLRRWHKSRLLQDSGGRLVGVPASHFVGVEEVQAFLQTYSQEVSLTADSRKSHLIFPQPNYADMLISQEGCEKNDSLLTSVDFHEYKNEADHGQQAPPNTDWRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLGGGAGTMGLSARYGPQFTLQHVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK","function_summary":"A single-pass cell-surface adhesion receptor that uses a multi-repeat cadherin ectodomain to form calcium-stabilized adhesive bonds between neighboring cells and a cytoplasmic tail that recruits catenins to couple adhesion to the actin cytoskeleton. By assembling adhesive and signaling complexes at the plasma membrane, it organizes and stabilizes neuronal contacts, promoting synapse assembly and sustaining chemical synaptic transmission through coordinated adhesion and cytoskeletal coupling.","plain_language":"PCDHGA8 has barely been studied. The model's best guess: A single-pass cell-surface adhesion receptor that uses a multi-repeat cadherin ectodomain to form calcium-stabilized adhesive bonds between neighboring cells and a cytoplasmic tail that recruits catenins to couple adhesion to the actin cytoskeleton. By assembling adhesive and signaling complexes at the plasma membrane, it organizes and stabilizes neuronal contacts, promoting synapse assembly and sustaining chemical synaptic transmission through coordinated adhesion and cytoskeletal coupling.","uniprot_summary":"Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the formation of multicellular aggregates.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0007416","label":"synapse assembly"},{"id":"GO:0007268","label":"chemical synaptic transmission"}],"cellular_component":[{"id":"GO:0005886","label":"plasma membrane"}]},"interpro":[{"id":"IPR015919","name":"Cadherin-like superfamily","type":"homologous_superfamily","start":29,"end":115},{"id":"IPR015919","name":"Cadherin-like superfamily","type":"homologous_superfamily","start":127,"end":234},{"id":"IPR015919","name":"Cadherin-like superfamily","type":"homologous_superfamily","start":230,"end":346},{"id":"IPR015919","name":"Cadherin-like superfamily","type":"homologous_superfamily","start":340,"end":444},{"id":"IPR015919","name":"Cadherin-like superfamily","type":"homologous_superfamily","start":441,"end":565},{"id":"IPR015919","name":"Cadherin-like superfamily","type":"homologous_superfamily","start":556,"end":666},{"id":"IPR002126","name":"Cadherin-like","type":"domain","start":19,"end":133},{"id":"IPR013164","name":"Cadherin, N-terminal","type":"domain","start":30,"end":112},{"id":"IPR002126","name":"Cadherin-like","type":"domain","start":134,"end":242},{"id":"IPR002126","name":"Cadherin-like","type":"domain","start":242,"end":347},{"id":"IPR002126","name":"Cadherin-like","type":"domain","start":356,"end":562},{"id":"IPR002126","name":"Cadherin-like","type":"domain","start":579,"end":682},{"id":"IPR032455","name":"Cadherin, cytoplasmic C-terminal domain","type":"domain","start":688,"end":772},{"id":"IPR031904","name":"Cadherin, C-terminal catenin-binding domain","type":"domain","start":811,"end":932},{"id":"IPR020894","name":"Cadherin conserved site","type":"conserved_site","start":230,"end":240},{"id":"IPR020894","name":"Cadherin conserved site","type":"conserved_site","start":440,"end":450},{"id":"IPR020894","name":"Cadherin conserved site","type":"conserved_site","start":550,"end":560}],"reasoning":"I begin by dissecting the InterPro architecture, which is dominated by tandem cadherin modules followed by a cytoplasmic tail specialized for cytoskeletal coupling. The extracellular region is built from multiple cadherin-like repeats: IPR015919 (Cadherin-like superfamily) spans residues 29–115, 127–234, 230–346, 340–444, and 441–565, and 556–666, with finer annotation by IPR002126 (Cadherin-like domain) at 19–133, 134–242, 242–347, 356–562, and 579–682. The N-terminal adhesive core is reinforced by IPR013164 (Cadherin, N-terminal domain) at 30–112, and two conserved calcium-binding/structural motifs—IPR020894 Cadherin conserved sites at 230–240 and 440–450—mark canonical cadherin repeats that rigidify the ectodomain in the presence of Ca2+. This extracellular array is followed by IPR032455 (Cadherin, cytoplasmic C-terminal domain, 688–772) and IPR031904 (Cadherin, C-terminal catenin-binding domain, 811–932), which together specify a cytosolic tail that recruits catenins and anchors the complex to the actin cytoskeleton. The ordered layout—N-terminal cadherin repeats for adhesion and Ca2+-stabilized ectodomains, a single-pass membrane anchor (implied between the extracellular and cytosolic regions), and a catenin-binding cytoplasmic tail—defines a classical cadherin architecture that causes high-avidity cell–cell adhesion and intracellular signal transduction.\n\nThis modular arrangement dictates molecular function. The tandem cadherin-like domains (IPR002126; IPR015919) create a rigid, Ca2+-stabilized adhesive surface that mediates homophilic and heterophilic binding between opposing cell membranes. The cytoplasmic C-terminal catenin-binding region (IPR031904) drives assembly of intracellular complexes that tune adhesion strength and signaling. Together, these features enforce multivalent protein–protein interactions rather than catalysis, aligning with GO:0005515 protein binding as the operative molecular function.\n\nFrom function to process, cadherin-mediated adhesion is a primary organizer of tissue architecture and neuronal connectivity. The adhesive ectodomain and catenin-coupled tail coordinate synapse initiation and stabilization, which mechanistically supports GO:0007416 synapse assembly. By stabilizing synaptic contacts and coupling to actin remodeling, the complex sustains vesicle tethering and receptor clustering, thereby supporting GO:0007268 chemical synaptic transmission. These processes are emergent properties of cadherin-driven adhesion and cytoskeletal coupling.\n\nCellular location follows directly from the architecture. The presence of a single-pass membrane topology with a large extracellular cadherin array and a cytosolic catenin-binding tail places the protein at the cell surface, consistent with GO:0005886 plasma membrane. The extracellular repeats face the intercellular space to engage neighboring cells, while the cytoplasmic tail interfaces with cortical actin.\n\nMechanistically, the protein likely forms trans-adhesive bonds via its cadherin ectodomains and cis-clusters within membrane microdomains. Calcium binding at the conserved cadherin sites rigidifies the ectodomain, increasing avidity and specificity of adhesion. The cytoplasmic tail recruits catenins (beta-catenin and p120-catenin) and alpha-catenin, which bridge to F-actin and mechanotransduction hubs. I therefore hypothesize interactions with catenins (CTNNB1, CTNND1, CTNNA isoforms), actin (ACTB/ACTG1), and synaptic scaffolds that assemble at cadherin-rich junctions. In neurons, these assemblies nucleate and stabilize synaptic contacts, coupling adhesion to synaptic assembly and neurotransmission.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q9Y5G5.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q9Y5G5"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q9Y5G5/entry","atlas":"/p/Q9Y5G5"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}