8djm
HMGCR-UBIAD1 Complex State 1
Structural highlights
FunctionHMDH_CRIGR Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis.[UniProtKB:P04035] Publication Abstract from PubMed3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the rate-limiting enzyme in cholesterol synthesis and target of cholesterol-lowering statin drugs. Accumulation of sterols in endoplasmic reticulum (ER) membranes accelerates degradation of HMGCR, slowing the synthesis of cholesterol. Degradation of HMGCR is inhibited by its binding to UBIAD1 (UbiA prenyltransferase domain-containing protein-1). This inhibition contributes to statin-induced accumulation of HMGCR, which limits their cholesterol-lowering effects. Here, we report cryo-electron microscopy structures of the HMGCR-UBIAD1 complex, which is maintained by interactions between transmembrane helix (TM) 7 of HMGCR and TMs 2-4 of UBIAD1. Disrupting this interface by mutagenesis prevents complex formation, enhancing HMGCR degradation. TMs 2-6 of HMGCR contain a 170-amino acid sterol sensing domain (SSD), which exists in two conformations-one of which is essential for degradation. Thus, our data supports a model that rearrangement of the TMs in the SSD permits recruitment of proteins that initate HMGCR degradation, a key reaction in the regulatory system that governs cholesterol synthesis. Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain.,Chen H, Qi X, Faulkner RA, Schumacher MM, Donnelly LM, DeBose-Boyd RA, Li X Nat Commun. 2022 Jul 25;13(1):4273. doi: 10.1038/s41467-022-32025-5. PMID:35879350[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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