8hf3 | pdb_00008hf3
Cryo-EM structure of human ZDHHC9/GCP16 complex
Structural highlights
DiseaseZDHC9_HUMAN Lujan-Fryns syndrome. The disease is caused by variants affecting the gene represented in this entry. FunctionZDHC9_HUMAN Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, such as ADRB2, HRAS, NRAS and CGAS (PubMed:16000296, PubMed:27481942, PubMed:37802025). The ZDHHC9-GOLGA7 complex is a palmitoyltransferase specific for HRAS and NRAS (PubMed:16000296). May have a palmitoyltransferase activity toward the beta-2 adrenergic receptor/ADRB2 and therefore regulate G protein-coupled receptor signaling (PubMed:27481942). Acts as a regulator of innate immunity by catalyzing palmitoylation of CGAS, thereby promoting CGAS homodimerization and cyclic GMP-AMP synthase activity (PubMed:37802025).[1] [2] [3] (Microbial infection) Through a sequential action with ZDHHC20, rapidly and efficiently palmitoylates SARS coronavirus-2/SARS-CoV-2 spike protein following its synthesis in the endoplasmic reticulum (ER). In the infected cell, promotes spike biogenesis by protecting it from premature ER degradation, increases half-life and controls the lipid organization of its immediate membrane environment. Once the virus has formed, spike palmitoylation controls fusion with the target cell.[4] Publication Abstract from PubMedPalmitoylation of cysteine residues at the C-terminal hypervariable regions in human HRAS and NRAS, which is necessary for RAS signaling, is catalyzed by the acyltransferase DHHC9 in complex with its accessory protein GCP16. The molecular basis for the acyltransferase activity and the regulation of DHHC9 by GCP16 is not clear. Here we report the cryo-electron microscopy structures of the human DHHC9-GCP16 complex and its yeast counterpart-the Erf2-Erf4 complex, demonstrating that GCP16 and Erf4 are not directly involved in the catalytic process but stabilize the architecture of DHHC9 and Erf2, respectively. We found that a phospholipid binding to an arginine-rich region of DHHC9 and palmitoylation on three residues (C24, C25 and C288) were essential for the catalytic activity of the DHHC9-GCP16 complex. Moreover, we showed that GCP16 also formed complexes with DHHC14 and DHHC18 to catalyze RAS palmitoylation. These findings provide insights into the regulatory mechanism of RAS palmitoyltransferases. Regulation of RAS palmitoyltransferases by accessory proteins and palmitoylation.,Yang A, Liu S, Zhang Y, Chen J, Fan Y, Wang F, Zou Y, Feng S, Wu J, Hu Q Nat Struct Mol Biol. 2024 Mar;31(3):436-446. doi: 10.1038/s41594-023-01183-5. , Epub 2024 Jan 5. PMID:38182928[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
