{"uniprot":"Q8IZF7","gene":"ADGRF2","name":"Adhesion G-protein coupled receptor F2","organism":"Homo sapiens (Human)","status":"dark","length":708,"sequence":"MGLTAYGNRRVQPGELPFGANLTLIHTRAQPVICSKLLLTKRVSPISFFLSKFQNSWGEDGWVQLDQLPSPNAVSSDQVHCSAGCTHRKCGWAASKSKEKVPARPHGVCDGVCTDYSQCTQPCPPDTQGNMGFSCRQKTWHKITDTCQTLNALNIFEEDSRLVQPFEDNIKISVYTGKSETITDMLLQKCPTDLSCVIRNIQQSPWIPGNIAVIVQLLHNISTAIWTGVDEAKMQSYSTIANHILNSKSISNWTFIPDRNSSYILLHSVNSFARRLFIDKHPVDISDVFIHTMGTTISGDNIGKNFTFSMRINDTSNEVTGRVLISRDELRKVPSPSQVISIAFPTIGAILEASLLENVTVNGLVLSAILPKELKRISLIFEKISKSEERRTQCVGWHSVENRWDQQACKMIQENSQQAVCKCRPSKLFTSFSILMSPHILESLILTYITYVGLGISICSLILCLSIEVLVWSQVTKTEITYLRHVCIVNIAATLLMADVWFIVASFLSGPITHHKGCVAATFFVHFFYLSVFFWMLAKALLILYGIMIVFHTLPKSVLVASLFSVGYGCPLAIAAITVAATEPGKGYLRPEICWLNWDMTKALLAFVIPALAIVVVNLITVTLVIVKTQRAAIGNSMFQEVRAIVRISKNIAILTPLLGLTWGFGVATVIDDRSLAFHIIFSLLNAFQVSPDASDQVQSERIHEDVL","function_summary":"A membrane-embedded adhesion-type G protein-coupled receptor that undergoes autoproteolytic priming and then transduces extracellular adhesion cues into intracellular G protein signaling. An N-terminal adhesion module and an internal autoproteolytic cassette generate a two-part receptor that maintains a tethered-agonist mechanism to activate the seven-helix signaling core. This coupling enables canonical pathways downstream of GPCR signaling at the cell surface, coordinating adhesion-dependent responses through heterotrimeric G protein engagement and β-arrestin–mediated control.","plain_language":"ADGRF2 has barely been studied. The model's best guess: A membrane-embedded adhesion-type G protein-coupled receptor that undergoes autoproteolytic priming and then transduces extracellular adhesion cues into intracellular G protein signaling. An N-terminal adhesion module and an internal autoproteolytic cassette generate a two-part receptor that maintains a tethered-agonist mechanism to activate the seven-helix signaling core.","uniprot_summary":"Orphan receptor.","go_terms":{"molecular_function":[{"id":"GO:0004930","label":"G protein-coupled receptor activity"}],"biological_process":[{"id":"GO:0007186","label":"G protein-coupled receptor signaling pathway"}],"cellular_component":[{"id":"GO:0016020","label":"membrane"}]},"interpro":[{"id":"IPR046338","name":"GAIN domain superfamily","type":"homologous_superfamily","start":287,"end":441},{"id":"IPR060341","name":"ADGRF2P/ADGRF4-like, N-terminal domain","type":"domain","start":104,"end":147},{"id":"IPR057244","name":"GAIN, subdomain B","type":"domain","start":293,"end":442},{"id":"IPR017981","name":"GPCR, family 2-like, 7TM","type":"domain","start":446,"end":689},{"id":"IPR051587","name":"Adhesion G protein-coupled receptor F","type":"family","start":117,"end":689},{"id":"IPR000832","name":"GPCR, family 2, secretin-like","type":"family","start":448,"end":472},{"id":"IPR000832","name":"GPCR, family 2, secretin-like","type":"family","start":520,"end":543},{"id":"IPR000832","name":"GPCR, family 2, secretin-like","type":"family","start":648,"end":668},{"id":"IPR000203","name":"GPS motif","type":"conserved_site","start":290,"end":439}],"reasoning":"I begin with the InterPro architecture and its order along the sequence. An N-terminal extracellular module is indicated by IPR060341 (ADGRF2P/ADGRF4-like, N-terminal domain, residues 104–147), which precedes a large adhesion GPCR hallmark: the GAIN region. This is captured by IPR046338 (GAIN domain superfamily, residues 287–441) and refined by IPR057244 (GAIN, subdomain B, residues 293–442). The GAIN fold is the catalytic scaffold that exposes an internal proteolytic site and drives an autoproteolytic event that splits the receptor into an N-terminal fragment (NTF) and a C-terminal fragment (CTF) that remain associated. The autoproteolysis is pinpointed by IPR000203 (GPS motif, conserved site, residues 290–439), which lies within the GAIN core and causes the characteristic cleavage that primes adhesion GPCR signaling. Immediately downstream, the seven-helix signaling module is defined by IPR017981 (GPCR, family 2-like, 7TM, residues 446–689). This transmembrane bundle is further classified as secretin-like class B by three overlapping family signatures: IPR000832 (GPCR, family 2, secretin-like, residues 448–520), IPR000832 (residues 520–543), and IPR000832 (residues 648–668). The broader lineage is reinforced by IPR051587 (Adhesion G protein-coupled receptor F family, residues 117–689), which ties the extracellular adhesion module to the intracellular 7TM signal-transduction core. Together, this ordered layout—NTF adhesion domain → GAIN/GPS autoproteolysis → class B 7TM—creates a receptor that couples extracellular matrix engagement to intracellular G protein activation.\n\nThis architecture dictates molecular function. The class B seven-transmembrane bundle (IPR017981 with secretin-like signatures) forms the G protein-coupled signaling core that binds heterotrimeric G proteins and catalyzes GDP-GTP exchange, establishing GO:0004930 G protein-coupled receptor activity. The GAIN/GPS system causes a constitutive tethered-agonist mechanism: cleavage within the GPS motif exposes an internal agonistic surface that biases the 7TM core toward active conformations. Thus, the N-terminal adhesion and autoproteolytic modules causally regulate the C-terminal GPCR switch.\n\nFrom this function, the biological process follows. Activation of heterotrimeric G proteins by the 7TM core initiates second-messenger cascades and kinase pathways, which is the essence of GO:0007186 G protein-coupled receptor signaling pathway. The adhesion GPCR F family signature (IPR051587) and the N-terminal ADGRF2P/ADGRF4-like domain (IPR060341) point to roles in cell–matrix adhesion and neurite dynamics; these inputs funnel into canonical GPCR signaling routes that modulate cytoskeletal and transcriptional responses.\n\nCellular location is determined by the presence of a multi-pass 7TM region and the extracellular NTF, which together enforce a membrane-embedded receptor. This supports GO:0016020 membrane and aligns with a multi-pass topology at the cell surface. The absence of soluble domains and the presence of the class B 7TM firmly place the protein as a membrane-resident signaling receptor.\n\nMechanistically, the NTF (adhesion domain) binds extracellular ligands or matrix, the GAIN/GPS cassette autoproteolytically primes the receptor, and the CTF’s class B 7TM core engages G proteins to drive signaling. I hypothesize that the receptor cycles between inactive and active states via a tethered-agonist mechanism, with intracellular loops and the 7TM C-terminal end coupling to Gα subunits. Likely interaction partners include heterotrimeric G proteins (Gs, Gi/o, or Gq depending on intracellular motifs), β-arrestins that bind phosphorylated intracellular tails to tune signaling and trafficking, and extracellular matrix components that dock onto the NTF. In neurons or adhesion-rich epithelia, this ensemble would coordinate adhesion cues with GPCR-mediated pathways at the plasma membrane.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q8IZF7.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q8IZF7"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q8IZF7/entry","atlas":"/p/Q8IZF7"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}