{"uniprot":"Q6PK18","gene":"OGFOD3","name":"2-oxoglutarate and iron-dependent oxygenase domain-containing protein 3","organism":"Homo sapiens (Human)","status":"dark","length":319,"sequence":"MAPQRRAATKAPEGNGAAERRNRSSTKKDRAPREVQRLWQRPWLRTAGLGAGFVLTALLLWSSLGADDGVAEVLARRGEVVAGRFIEVPCSEDYDSHRRFEGCTPRKCGRGVTDVVITREEAERIRSVAEKGLSLGGSDGGASILDLHSGALSVGKHFVNLYRYFGDKIQNIFSEEDFRLYREVRQKVQLTIAEAFGISASSLHLTKPTFFSRINSTEARTAHDEYWHAHVDKVTYGSFDYTSLLYLSNYLEDFGGGRFMFMEEGANKTVEPRAGRVSFFTSGSENLHRVEKVHWGTRYAITIAFSCNPDHGIEDPAFP","function_summary":"A soluble Fe(II)/2-oxoglutarate-dependent oxygenase that installs 4-hydroxyproline on protein substrates. Its catalytic core uses iron and 2-oxoglutarate to hydroxylate proline residues, thereby tuning protein stability and interaction properties. Although intrinsically soluble, it likely operates near membranes by docking onto membrane-proximal assemblies to access its targets, coupling localized hydroxylation to broader cellular pathways.","plain_language":"OGFOD3 has barely been studied. The model's best guess: A soluble Fe(II)/2-oxoglutarate-dependent oxygenase that installs 4-hydroxyproline on protein substrates. Its catalytic core uses iron and 2-oxoglutarate to hydroxylate proline residues, thereby tuning protein stability and interaction properties.","uniprot_summary":"Probable prolyl 4-hydroxylase.","go_terms":{"molecular_function":[{"id":"GO:0031545","label":"peptidyl-proline 4-dioxygenase activity"},{"id":"GO:0016706","label":"2-oxoglutarate-dependent dioxygenase activity"}],"biological_process":[{"id":"GO:0019511","label":"peptidyl-proline hydroxylation"}],"cellular_component":[{"id":"GO:0016020","label":"membrane"}]},"interpro":[{"id":"IPR006620","name":"Prolyl 4-hydroxylase, alpha subunit","type":"domain","start":108,"end":306},{"id":"IPR005123","name":"Oxoglutarate/iron-dependent dioxygenase domain","type":"domain","start":207,"end":309},{"id":"IPR044862","name":"Prolyl 4-hydroxylase alpha subunit, Fe(2+) 2OG dioxygenase domain","type":"domain","start":223,"end":303},{"id":"IPR039210","name":"2-oxoglutarate and iron-dependent oxygenase domain-containing protein 3","type":"family","start":1,"end":318}],"reasoning":"I begin with the InterPro architecture. The polypeptide is covered end-to-end by IPR039210 (2-oxoglutarate and iron-dependent oxygenase domain-containing protein 3 family, residues 1–318), establishing membership in a conserved oxygenase family. Within this scaffold, IPR006620 (Prolyl 4-hydroxylase, alpha subunit domain, residues 108–306) defines a canonical prolyl 4-hydroxylase-like core that specializes in post-translational modification of proline residues in proteins. Nested more distally, IPR005123 (Oxoglutarate/iron-dependent dioxygenase domain, residues 207–309) and IPR044862 (Prolyl 4-hydroxylase alpha subunit, Fe(2+) 2OG dioxygenase domain, residues 223–303) pinpoint the catalytic heart: a Fe(II)/2-oxoglutarate (2OG)-dependent dioxygenase module. The ordered layout—an N-terminal family envelope, a central prolyl 4-hydroxylase-like domain, and a tightly defined Fe(II)/2OG catalytic core—causally dictates a chemistry that uses Fe(II) and 2OG to hydroxylate peptidyl-proline, releasing succinate and CO2.\n\nThis domain architecture compels a molecular function of peptidyl-proline 4-dioxygenase activity (GO:0031545) and more generally a 2-oxoglutarate-dependent dioxygenase activity (GO:0016706). The prolyl 4-hydroxylase-like fold (IPR006620) and the Fe(II)/2OG catalytic center (IPR005123, IPR044862) together specify site-selective hydroxylation of proline side chains in protein substrates. Such chemistry directly drives the biological process of peptidyl-proline hydroxylation (GO:0019511), a modification that tunes protein stability, folding, and interaction surfaces.\n\nThe absence of transmembrane helices in the annotated domains suggests a soluble enzyme, yet the functional context and cellular component label indicate membrane association. A parsimonious explanation is peripheral or transient membrane association via protein–protein interactions that recruit the soluble Fe(II)/2OG enzyme to membrane-proximal assemblies. This reasoning supports a membrane localization (GO:0016020), plausibly at cytoplasmic-facing membranes where substrate proteins and assembly factors concentrate.\n\nMechanistically, the enzyme binds Fe(II) and 2OG within the IPR044862-defined pocket, activates O2 to form a ferryl intermediate, and inserts a hydroxyl group at the 4-position of peptidyl-proline. This reaction modifies target proteins and can nucleate higher-order assemblies. From this, I hypothesize that the enzyme transiently associates with membrane-proximal protein complexes—such as cytoskeletal or trafficking hubs—to access substrates. Likely interaction partners include proline-rich membrane-associated proteins and scaffolds that localize hydroxylase chemistry near membranes. Such assemblies would stabilize the enzyme at the membrane interface and channel modified substrates into downstream pathways.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q6PK18.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q6PK18"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q6PK18/entry","atlas":"/p/Q6PK18"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}