{"uniprot":"Q96GR4","gene":"ZDHHC12","name":"Probable palmitoyltransferase ZDHHC12","organism":"Homo sapiens (Human)","status":"dark","length":267,"sequence":"MAPWALLSPGVLVRTGHTVLTWGITLVLFLHDTELRQWEEQGELLLPLTFLLLVLGSLLLYLAVSLMDPGYVNVQPQPQEELKEEQTAMVPPAIPLRRCRYCLVLQPLRARHCRECRRCVRRYDHHCPWMENCVGERNHPLFVVYLALQLVVLLWGLYLAWSGLRFFQPWGQWLRSSGLLFATFLLLSLFSLVASLLLVSHLYLVASNTTTWEFISSHRIAYLRQRPSNPFDRGLTRNLAHFFCGWPSGSWETLWAEEEEEGSSPAV","function_summary":"A human multi-pass membrane acyltransferase that installs long-chain fatty acids onto cysteine residues of target proteins to regulate their membrane association and trafficking. Operating at the endoplasmic reticulum and Golgi apparatus, it catalyzes reversible lipidation that modulates cytoskeletal, exocytotic, and signaling pathways. By forming a transient acyl-enzyme intermediate and transferring palmitate from acyl-CoA donors to substrates such as myosin VIIA, syntaxin-4, SNAP27, and a membrane-anchored acyl carrier, it orchestrates protein palmitoylation within ER–Golgi trafficking corridors.","plain_language":"ZDHHC12 has barely been studied. The model's best guess: A human multi-pass membrane acyltransferase that installs long-chain fatty acids onto cysteine residues of target proteins to regulate their membrane association and trafficking. Operating at the endoplasmic reticulum and Golgi apparatus, it catalyzes reversible lipidation that modulates cytoskeletal, exocytotic, and signaling pathways.","uniprot_summary":"Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates. Has a palmitoyltransferase activity toward myosin VIIA, syntaxin-4, SNAP27 and N-myristoyl-N-alkyltransferase.","go_terms":{"molecular_function":[{"id":"GO:0016409","label":"palmitoyltransferase activity"}],"biological_process":[{"id":"GO:0018345","label":"protein palmitoylation"}],"cellular_component":[{"id":"GO:0005794","label":"Golgi apparatus"},{"id":"GO:0005783","label":"endoplasmic reticulum"}]},"interpro":[{"id":"IPR001594","name":"Palmitoyltransferase, DHHC domain","type":"domain","start":97,"end":216},{"id":"IPR039859","name":"Palmitoyltransferase PFA4/ZDHHC16/ZDHHC20/ERF2-like","type":"family","start":25,"end":248}],"reasoning":"I begin with the InterPro architecture. The core catalytic module is IPR001594 (Palmitoyltransferase, DHHC domain, residues 97–216), a cysteine-rich, membrane-embedded acyltransferase fold that centers on the invariant Asp-His-His-Cys motif. This DHHC catalytic cassette typically sits within multiple transmembrane helices and forms an acyl-enzyme intermediate that drives S-acylation chemistry. Encompassing and extending around this core is IPR039859 (Palmitoyltransferase PFA4/ZDHHC16/ZDHHC20/ERF2-like family, residues 25–248), which defines a clade of endoplasmic reticulum/Golgi-resident S-acyltransferases. The ordered layout—an N-terminal membrane-anchoring region feeding into a central DHHC catalytic block and flanked by additional transmembrane segments—creates a multi-pass membrane enzyme optimized for acyl transfer within the lipid bilayer.\n\nThis DHHC-centered architecture dictates the molecular function. The cysteine-rich DHHC domain catalyzes transfer of long-chain fatty acyl groups from acyl-CoA donors to cysteine residues of substrate proteins, establishing GO:0016409 palmitoyltransferase activity. The membrane-embedded active site and the conserved catalytic tetrad cause thioester formation and acyl-enzyme chemistry that underlies reversible protein S-palmitoylation.\n\nFrom this chemistry, the biological process follows directly. By installing thioester-linked fatty acids onto cytosolic cysteines, the enzyme executes GO:0018345 protein palmitoylation. This modification tunes membrane affinity, trafficking, and signaling of diverse substrates. The provided substrate spectrum—myosin VIIA, syntaxin-4, SNAP27, and N-myristoyl-N-alkyltransferase—illustrates a broad functional reach: myosin VIIA links to cytoskeletal dynamics; syntaxin-4 and SNAP27 are exocytosis/secretory pathway nodes; and the N-myristoyl-N-alkyltransferase (a membrane-anchored acyl carrier) situates the enzyme at lipidation hubs that coordinate acyl flux.\n\nCellular location is encoded by both the family signature and the membrane-embedded catalytic core. Members of the IPR039859 family predominantly operate at the endoplasmic reticulum and Golgi apparatus. The multi-pass membrane topology and the need to access nascent and recycling membrane proteins anchor the enzyme to GO:0005783 endoplasmic reticulum and GO:0005794 Golgi apparatus. This ER–Golgi distribution enables early substrate encounter and subsequent trafficking-dependent substrate selection.\n\nMechanistically, the enzyme likely follows the canonical ping-pong pathway of DHHC acyltransferases: autoacylation of the catalytic cysteine to form a thioester intermediate, followed by transacylation to substrate cysteines. Substrate selection is enforced by membrane proximity and local binding grooves that recognize cytosolic loops of target proteins. At the ER and Golgi, this positioning allows rapid palmitoylation of trafficking and signaling factors.\n\nGiven this mechanistic and spatial framework, I hypothesize interaction with substrates and pathway partners that concentrate at ER–Golgi interfaces. Direct contacts with myosin VIIA, syntaxin-4, and SNAP27 are expected. Additional transient associations are likely with acyl-CoA–producing enzymes and ER/Golgi scaffolds that stabilize DHHC enzymes, such as accessory factors analogous to accessory acyltransferase partners and COPII/COPI coat components that modulate substrate trafficking. Together, these interactions create a palmitoylation hub that tunes membrane-associated signaling and transport.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q96GR4.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q96GR4"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q96GR4/entry","atlas":"/p/Q96GR4"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}