{"uniprot":"Q68DD2","gene":"PLA2G4F","name":"Cytosolic phospholipase A2 zeta","organism":"Homo sapiens (Human)","status":"dark","length":849,"sequence":"MLWALWPRWLADKMLPLLGAVLLQKREKRGPLWRHWRRETYPYYDLQVKVLRATNIRGTDLLSKADCYVQLWLPTASPSPAQTRIVANCSDPEWNETFHYQIHGAVKNVLELTLYDKDILGSDQLSLLLFDLRSLKCGQPHKHTFPLNHQDSQELQVEFVLEKSQVPASEVITNGVLVAHPCLRIQGTLRGDGTAPREEYGSRQLQLAVPGAYEKPQLLPLQPPTEPGLPPTFTFHVNPVLSSRLHVELMELLAAVQSGPSAELEAQTSKLGEGGILLSSLPLGQEEQCSVALGEGQEVALSMKVEMSSGDLDLRLGFDLSDGEQEFLDRRKQVVSKALQQVLGLSEALDSGQVPVVAVLGSGGGTRAMSSLYGSLAGLQELGLLDTVTYLSGVSGSTWCISTLYRDPAWSQVALQGPIERAQVHVCSSKMGALSTERLQYYTQELGVRERSGHSVSLIDLWGLLVEYLLYQEENPAKLSDQQEAVRQGQNPYPIYTSVNVRTNLSGEDFAEWCEFTPYEVGFPKYGAYVPTELFGSELFMGRLLQLQPEPRICYLQGMWGSAFATSLDEIFLKTAGSGLSFLEWYRGSVNITDDCQKPQLHNPSRLRTRLLTPQGPFSQAVLDIFTSRFTSAQSFNFTRGLCLHKDYVAGREFVAWKDTHPDAFPNQLTPMRDCLYLVDGGFAINSPFPLALLPQRAVDLILSFDYSLEAPFEVLKMTEKYCLDRGIPFPSIEVGPEDMEEARECYLFAKAEDPRSPIVLHFPLVNRTFRTHLAPGVERQTAEEKAFGDFVINRPDTPYGMMNFTYEPQDFYRLVALSRYNVLNNVETLKCALQLALDRHQARERAGA","function_summary":"A cytosolic, calcium-responsive phospholipase/lysophospholipase that transiently docks onto cytosolic membrane surfaces via a C2 module and hydrolyzes the sn-1 ester of membrane phospholipids and their lyso-derivatives. By generating lysophospholipids and free fatty acids that feed reacylation cycles, it drives membrane lipid remodeling and supports pathways that maintain phosphatidylglycerol balance. Its soluble architecture and Ca2+-regulated membrane targeting position it in the cytoplasm where it coordinates with lipid-metabolic assemblies to tune membrane composition.","plain_language":"PLA2G4F has barely been studied. The model's best guess: A cytosolic, calcium-responsive phospholipase/lysophospholipase that transiently docks onto cytosolic membrane surfaces via a C2 module and hydrolyzes the sn-1 ester of membrane phospholipids and their lyso-derivatives. By generating lysophospholipids and free fatty acids that feed reacylation cycles, it drives membrane lipid remodeling and supports pathways that maintain phosphatidylglycerol balance.","uniprot_summary":"Calcium-dependent phospholipase A1 that catalyzes the hydrolysis of phospholipids and lysophospholipids.","go_terms":{"molecular_function":[{"id":"GO:0008970","label":"phospholipase A1 activity"}],"biological_process":[{"id":"GO:0046471","label":"phosphatidylglycerol metabolic process"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"}]},"interpro":[{"id":"IPR035892","name":"C2 domain superfamily","type":"homologous_superfamily","start":42,"end":162},{"id":"IPR016035","name":"Acyl transferase/acyl hydrolase/lysophospholipase","type":"homologous_superfamily","start":313,"end":834},{"id":"IPR000008","name":"C2 domain","type":"domain","start":27,"end":147},{"id":"IPR041847","name":"Cytosolic phospholipase A2, C2 domain","type":"domain","start":46,"end":163},{"id":"IPR040723","name":"Cytosolic phospholipases A2, C2-domain","type":"domain","start":184,"end":304},{"id":"IPR002642","name":"Lysophospholipase, catalytic domain","type":"domain","start":286,"end":849},{"id":"IPR065447","name":"Lysophospholipase-like","type":"family","start":65,"end":844}],"reasoning":"I begin with the InterPro architecture. The N-terminus contains a canonical calcium/lipid-binding module: IPR000008 (C2 domain, residues 27–147) sits within IPR035892 (C2 domain superfamily, residues 42–162) and is further specified by IPR041847 (Cytosolic phospholipase A2, C2 domain, residues 46–163). This tandem of general and cytosolic phospholipase A2–specific C2 signatures indicates a Ca2+-responsive membrane-targeting module that transiently docks the enzyme onto anionic phospholipid surfaces. A second C2-related annotation, IPR040723 (Cytosolic phospholipases A2, C2-domain, residues 184–304), suggests an extended C2-associated region that stabilizes membrane association and positions the catalytic core.\n\nThe central-to-C-terminal half is dominated by lysophospholipase chemistry. IPR016035 (Acyl transferase/acyl hydrolase/lysophospholipase superfamily, residues 313–834) and IPR002642 (Lysophospholipase, catalytic domain, residues 286–849) define a serine-dependent hydrolase fold that cleaves ester bonds in glycerophospholipids and lysophospholipids. IPR065447 (Lysophospholipase-like family, residues 65–844) reinforces that this is a cytosolic lysophospholipase-like scaffold rather than a secreted PLA2. The ordered layout—an N-terminal Ca2+-regulated membrane-targeting C2 platform feeding into a large lysophospholipase catalytic core—causally establishes a phospholipase/lysophospholipase enzyme that acts on membrane phospholipids and their lyso-derivatives.\n\nFrom this architecture, the molecular function resolves as phospholipase A1 chemistry. The catalytic core and known substrate preferences of lysophospholipase-like folds support GO:0008970 phospholipase A1 activity, with the C2 module ensuring Ca2+-triggered access to bilayers where sn-1 hydrolysis is favored. The enzyme’s ability to hydrolyze both phospholipids and lysophospholipids is explained by the shared lysophospholipase fold and its accommodation of acyl chains at different positions.\n\nThis chemistry directly feeds into phospholipid remodeling pathways. Hydrolysis and reacylation cycles govern glycerophospholipid pools; thus the enzyme’s activity drives GO:0046471 phosphatidylglycerol metabolic process and more broadly the Lands cycle that maintains membrane composition. The C2-guided membrane engagement ensures that catalysis occurs at the cytosolic face of organelle membranes rather than in soluble space.\n\nCellular location follows from the soluble enzyme architecture and Ca2+-regulated membrane docking. The absence of transmembrane segments and the presence of soluble C2 and lysophospholipase domains indicate a cytosolic enzyme that transiently associates with membranes. This supports GO:0005829 cytosol and aligns with a broader cytoplasmic residency.\n\nMechanistically, Ca2+ binding to the N-terminal C2 domain triggers membrane recruitment and proper orientation of the catalytic groove. The enzyme then cleaves the sn-1 ester of phospholipids and lysophospholipids, generating lysophospholipids and free fatty acids that feed into reacylation pathways. Likely interaction partners include cytosolic lipid-metabolic assemblies: acyl-CoA–handling enzymes and membrane-remodeling factors that channel products into phosphatidylglycerol and related pathways. I hypothesize transient complexes with acyl-CoA synthetases and lysophospholipid acyltransferases to couple hydrolysis with rapid reacylation, and with Ca2+-sensing adaptors that tune membrane association dynamics.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q68DD2.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q68DD2"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q68DD2/entry","atlas":"/p/Q68DD2"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}