{"uniprot":"C9J798","gene":"RASA4B","name":"Ras GTPase-activating protein 4B","organism":"Homo sapiens (Human)","status":"dark","length":803,"sequence":"MAKRSSLYIRIVEGKNLPAKDITGSSDPYCIVKVDNEPIIRTATVWKTLCPFWGEEYQVHLPPTFHAVAFYVMDEDALSRDDVIGKVCLTRDTIASHPKGFSGWAHLTEVDPDEEVQGEIHLRLEVWPGARACRLRCSVLEARDLAPKDRNGTSDPFVRVRYKGRTRETSIVKKSCYPRWNETFEFELQEGAMEALCVEAWDWDLVSRNDFLGKVVIDVQRLRVVQQEEGWFRLQPDQSKSRRHDEGNLGSLQLEVRLRDETVLPSSYYQPLVHLLCHEVKLGMQGPGQLIPLIEETTSTECRQDVATNLLKLFLGQGLAKDFLDLLFQLELSRTSETNTLFRSNSLASKSVESFLKVAGMQYLHGVLGPIINKVFEEKKYVELDPSKVEVKDVGCSGLHRPQTEAEVLEQSAQTLRAHLGALLSALSRSVRACPAVVRATFRQLFRRVRERFPGAQHENVPFIAVTSFLCLRFFSPAIMSPKLFHLRERHADARTSRTLLLLAKAVQNVGNMDTPASRAKEAWMEPLQPTVHQGVAQLKDFITKLVDIEEKDELDLQRTLSLQAPPVKEGPLFIHRTKGKGPLMSSSFKKLYFSLTTEALSFAKTPSSKKSALIKLANIRAAEKVEEKSFGGSHVMQVIYTDDAGRPQTAYLQCKCVNELNQWLSALRKVSINNTGLLGSYHPGVFRGDKWSCCHQKEKTGQGCDKTRSRVTLQEWNDPLDHDLEAQLIYRHLLGVEAMLWERHRELSGGAEAGTVPTSPGKVPEDSLARLLRVLQDLREAHSSSPAGSPPSEPNCLLELQT","function_summary":"A calcium-regulated small GTPase-activating scaffold that cycles between the cytosol and the plasma membrane. Tandem calcium-sensitive membrane-targeting modules recruit the protein to anionic lipid patches, where a central catalytic core accelerates GTP hydrolysis on membrane-proximal small GTPases. A C-terminal lipid- and zinc-binding tail stabilizes membrane association and tunes signaling specificity. Through this spatially controlled inactivation of GTPases, it dampens downstream pathways that coordinate cytoskeletal remodeling and receptor-driven signaling during cellular responses to calcium.","plain_language":"RASA4B has barely been studied. The model's best guess: A calcium-regulated small GTPase-activating scaffold that cycles between the cytosol and the plasma membrane. Tandem calcium-sensitive membrane-targeting modules recruit the protein to anionic lipid patches, where a central catalytic core accelerates GTP hydrolysis on membrane-proximal small GTPases.","uniprot_summary":"Possible calcium-regulated GTPase-activating protein.","go_terms":{"molecular_function":[{"id":"GO:0005096","label":"GTPase activator activity"}],"biological_process":[{"id":"GO:0034260","label":"negative regulation of GTPase activity"},{"id":"GO:0071277","label":"cellular response to calcium ion"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0005886","label":"plasma membrane"}]},"interpro":[{"id":"IPR035892","name":"C2 domain superfamily","type":"homologous_superfamily","start":2,"end":266},{"id":"IPR008936","name":"Rho GTPase activation protein","type":"homologous_superfamily","start":264,"end":608},{"id":"IPR011993","name":"PH-like domain superfamily","type":"homologous_superfamily","start":562,"end":713},{"id":"IPR000008","name":"C2 domain","type":"domain","start":1,"end":105},{"id":"IPR000008","name":"C2 domain","type":"domain","start":116,"end":234},{"id":"IPR001936","name":"Ras GTPase-activating domain","type":"domain","start":244,"end":605},{"id":"IPR037777","name":"RASA4, PH domain","type":"domain","start":542,"end":681},{"id":"IPR001849","name":"Pleckstrin homology domain","type":"domain","start":566,"end":675},{"id":"IPR039360","name":"Ras GTPase-activating protein","type":"family","start":21,"end":774},{"id":"IPR023152","name":"Ras GTPase-activating protein, conserved site","type":"conserved_site","start":468,"end":482},{"id":"IPR001562","name":"Zinc finger, Btk motif","type":"conserved_site","start":675,"end":711}],"reasoning":"I begin by dissecting the domain architecture. The N-terminus carries two C2 modules: IPR000008 (C2 domain, residues 1–105) followed by IPR000008 (C2 domain, residues 116–234), encompassed by IPR035892 (C2 domain superfamily, residues 2–266). Tandem C2 domains create a calcium-regulated membrane-targeting clamp; Ca2+ coordination in C2 folds promotes electrostatic engagement with acidic phospholipids, thereby gating reversible association with membranes. Immediately downstream lies a central catalytic core defined by IPR001936 (Ras GTPase-activating domain, residues 244–605) and its broader scaffold IPR008936 (Rho GTPase activation protein homologous superfamily, residues 264–608), with IPR039360 (Ras GTPase-activating protein family, residues 21–774) and the catalytic hallmark IPR023152 (Ras GTPase-activating protein, conserved site, residues 468–482). This architecture encodes a GAP module that accelerates GTP hydrolysis on small GTPases by stabilizing the transition state and positioning catalytic residues. The C-terminus transitions into lipid-binding and signaling modules: IPR011993 (PH-like domain superfamily, residues 562–713) and IPR001849 (Pleckstrin homology domain, residues 566–675), with a lineage-specific signature IPR037777 (RASA4, PH domain, residues 542–681). The extreme C-terminus contains IPR001562 (Zinc finger, Btk motif, residues 675–711), a PH-associated zinc-binding element that fine-tunes membrane and protein interactions. Together, the ordered layout—tandem C2 membrane clamp, central RasGAP engine, and C-terminal PH/Btk membrane-sensing tail—creates a Ca2+-tunable, membrane-recruitable GTPase-activating scaffold.\n\nFrom this architecture, the molecular function resolves as GO:0005096 GTPase activator activity. The RasGAP domain (IPR001936) and its conserved catalytic site (IPR023152) cause stimulation of GTP hydrolysis on Ras-family and related small GTPases, turning them off. The tandem C2 and PH/Btk modules do not catalyze chemistry themselves but enforce spatial control: they dock the GAP core at specific membrane microdomains where substrates reside.\n\nThis catalytic shutoff propagates to biological process. By accelerating GTP hydrolysis on small GTPases, the protein executes GO:0034260 negative regulation of GTPase activity—switching off pathways that drive actin remodeling, vesicle trafficking, and MAPK signaling. The C2 clamp’s Ca2+-dependent membrane affinity couples the GAP’s action to calcium signals, embedding the protein in GO:0071277 cellular response to calcium ion. Calcium spikes recruit the tandem C2 domains and the PH/Btk tail, synchronizing GTPase inactivation with receptor-proximal signaling and cytoskeletal responses.\n\nCellular location follows directly from the targeting modules. The tandem C2 domains and PH/Btk tail drive reversible membrane association, while the absence of transmembrane helices supports a soluble baseline. This yields a dynamic partition between GO:0005829 cytosol and GO:0005886 plasma membrane. In resting conditions, the protein remains cytosolic; upon Ca2+ elevation and phosphoinositide production, it accumulates at the plasma membrane to inactivate membrane-proximal GTPases.\n\nMechanistically, I hypothesize a Ca2+-gated membrane recruitment cycle. Calcium binding to the N-terminal C2 tandem exposes lipid-binding surfaces, docking the protein at anionic membrane patches. The central RasGAP domain then engages membrane-anchored small GTPases, while the C-terminal PH/Btk module stabilizes the complex and biases localization toward phosphoinositide-rich nanodomains. Likely interaction partners include membrane-proximal small GTPases and their effectors: Ras-family substrates at the cell surface, Src-family kinases and adaptor complexes that generate PI3K products, and actin-regulatory assemblies. This ensemble positions the GAP to terminate signaling pulses with high spatial fidelity at the plasma membrane while remaining soluble in the cytosol when signaling subsides.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-C9J798.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/C9J798"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/C9J798/entry","atlas":"/p/C9J798"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}