{"uniprot":"A4FU28","gene":"CTAGE9","name":"cTAGE family member 9","organism":"Homo sapiens (Human)","status":"dark","length":777,"sequence":"MEEPGATPQPYLGLVLEELGRVVAALPESMRPDENPYGFPSELVVCAAVIGFFVVLLFLWRSFRSVRSRLYVGREQKLGATLSGLIEEKCKLLEKFSLIQKEYEGYEVESSLEDASFEKAAAEEARSLEATCEKLSRSNSELEDEILCLEKDLKEEKSKHSQQDELMADISKSIQSLEDESKSLKSQIAEAKIICKTFKMSEERRAIAIKDALNENSQLQTSHKQLFQQEAEVWKGQVSELNKQKITFEDSKVHAEQVLNDKENHIKTLTGHLPMMKDQAAVLEEDTTDDDNLELKVNSQWENGANLDDPPKGALKKLIHAAKLNVSLKSLEGERNHIIIQLSEVDKTKEELTEHIKNLQTQQASLQSENIYFESENQKLQQKLKIMTEFYQENEMKLYRKLTVEENYRIEEEEKLSRVEEKISHATEELETYRKLAKDLEEELERTVHFYQKQVISYEKRGHDNWLAARTAERNLSDLRKENAHNKQKLTERELKFELLEKDPNALDVSNTAFGREHSPCSPSPLGRPSSETRAFPSPQTLLEDPLRLSPVLPGGGGRGPSSPGNPLDHQITNERGEPSYDRLIDPHRAPSDTGSLSSPVEQDRRMMFPPPGQSYPDSTLPPQREDRFYSNSERLSGPAEPRSFKMTSLDKMDRSMPSEMESSRNDAKDDLGNLNVPDSSLPAENEATGPGLIPPPLAPISGPLFPVDTRGPFMRRGPPFPPPPPGTMFGASRGYFPPRDFPGPPHAPFAMRNIYPPRGLPPYLHPRPGFYPNPTF","function_summary":"A human ER-associated scaffold that uses an extended coiled-coil to assemble membrane-proximal complexes controlling protein quality and signaling. By organizing ER-resident degradation and trafficking modules, it promotes ER-associated degradation and regulated protein exit from the ER, steers membrane targeting pathways, and supports autophagy. Its ER-anchored assemblies also potentiate innate immune signaling and transcriptional programs, consistent with a predominantly ER-membrane localization and a dynamic cytoplasmic pool that coordinates proteostasis with NF-κB–dependent responses.","plain_language":"CTAGE9 has barely been studied. The model's best guess: A human ER-associated scaffold that uses an extended coiled-coil to assemble membrane-proximal complexes controlling protein quality and signaling. By organizing ER-resident degradation and trafficking modules, it promotes ER-associated degradation and regulated protein exit from the ER, steers membrane targeting pathways, and supports autophagy.","uniprot_summary":"Involved in endoplasmic reticulum-associated degradation (ERAD).","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:1903829","label":"positive regulation of signal transduction"},{"id":"GO:0045087","label":"innate immune response"},{"id":"GO:0010508","label":"positive regulation of autophagy"},{"id":"GO:0006612","label":"protein targeting to membrane"},{"id":"GO:0051092","label":"positive regulation of NF-kappaB transcription factor activity"},{"id":"GO:0046822","label":"regulation of nucleocytoplasmic transport"},{"id":"GO:0043123","label":"positive regulation of I-kappaB kinase/NF-kappaB signaling"},{"id":"GO:0006357","label":"regulation of transcription by RNA polymerase II"},{"id":"GO:0030433","label":"ubiquitin-dependent ERAD pathway"},{"id":"GO:0070861","label":"regulation of protein exit from endoplasmic reticulum"}],"cellular_component":[{"id":"GO:0005789","label":"endoplasmic reticulum membrane"}]},"interpro":[{"id":"IPR064057","name":"MIA2/CTAGE5, coiled-coil domain","type":"domain","start":35,"end":775},{"id":"IPR051500","name":"cTAGE and MIA/OTOR","type":"family","start":20,"end":776}],"reasoning":"I begin with the InterPro architecture. The polypeptide carries IPR064057 (MIA2/CTAGE5, coiled-coil domain, residues 35–775), an extended coiled-coil scaffold that typically mediates oligomerization and multivalent assembly of membrane-proximal complexes. This long coiled-coil is embedded within IPR051500 (cTAGE and MIA/OTOR family, residues 20–776), a family signature that defines ER-associated assembly factors that organize cargo selection and membrane-proximal quality control. The ordered layout—an N-to-C continuous coiled-coil superstructure spanning nearly the entire protein—causes avid protein–protein interactions and stable tethering to endoplasmic reticulum (ER) surfaces rather than catalytic chemistry. This architecture therefore dictates a molecular function centered on GO:0005515 protein binding.\n\nA coiled-coil ER-tether that nucleates large assemblies naturally drives several ER-centered processes. First, by stabilizing ER-associated degradation (ERAD) platforms, it promotes the ubiquitin-dependent ERAD pathway (GO:0030433) and regulates protein exit from the ER (GO:0070861). The cTAGE/MIA family is known to scaffold ERAD by recruiting ubiquitin ligases and extraction machinery; the extended coiled-coil provides the physical basis for assembling these modules and accelerating retrotranslocation and proteasomal delivery. Second, the same scaffold can bias membrane targeting and vesicular flow emanating from the ER, explaining roles in protein targeting to membrane (GO:0006612) and positive regulation of intracellular signal transduction (GO:1903829). Third, ER stress and innate immune signaling converge at ER–membrane interfaces; by organizing signaling adaptors and trafficking hubs, this scaffold can potentiate NF-κB pathway activation, aligning with positive regulation of NF-kappaB transcription factor activity (GO:0051092) and positive regulation of I-kappaB kinase/NF-kappaB signaling (GO:0043123). Its influence on nucleocytoplasmic transport (GO:0046822) and transcriptional programs (GO:0006357) follows from ER-to-nucleus communication and NF-κB–dependent transcription. Finally, ER-derived autophagic routes and selective autophagy are coordinated at ER subdomains; by stabilizing ER–phagophore interfaces, the scaffold supports positive regulation of autophagy (GO:0010508). Together, these processes cohere around an ER-anchored organizer that couples membrane trafficking, proteostasis, and innate immune signaling.\n\nCellular localization follows directly from the domain logic and process coupling. The coiled-coil ER-tether and cTAGE/MIA family identity place the protein at the endoplasmic reticulum membrane (GO:0005789), where it assembles and regulates ERAD and membrane-targeting machinery. Its soluble scaffold nature and broad interaction footprint also justify a cytoplasmic pool that dynamically associates with ER surfaces.\n\nMechanistically, I hypothesize that the protein forms a high-avidity ER platform that recruits ERAD E3 ligases and extraction factors, tunes ER-to-membrane cargo flow, and nucleates innate immune signaling assemblies. Likely partners include ERAD core components (e.g., SEL1L–HRD1 and DERL proteins), COPII/COPI and COA machinery for membrane targeting, autophagy initiators at ER–phagophore contacts, and NF-κB pathway adaptors. Through these assemblies, it coordinates proteostasis with immune and transcriptional outputs.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-A4FU28.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/A4FU28"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/A4FU28/entry","atlas":"/p/A4FU28"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}