8DJK

HMGCR-UBIAD1 Complex State 2

Summary for 8DJK

• Entry DOI: 10.2210/pdb8djk/pdb
• EMDB information: 27460
• Descriptor: 3-hydroxy-3-methylglutaryl-coenzyme A reductase, UbiA prenyltransferase domain-containing protein 1, Soluble cytochrome b562, ... (7 entities in total)
• Functional Keywords: cholesterol, membrane protein, oxidoreductase-immune system complex, oxidoreductase/immune system
• Biological source: Cricetulus griseus (Chinese hamster); More
• Total number of polymer chains: 5
• Total formula weight: 141394.51

Authors

Chen, H.,Qi, X.,Li, X. (deposition date: 2022-06-30, release date: 2022-08-03, Last modification date: 2024-10-23)

Primary citation

Chen, H.,Qi, X.,Faulkner, R.A.,Schumacher, M.M.,Donnelly, L.M.,DeBose-Boyd, R.A.,Li, X.
Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain.
Nat Commun, 13:4273-4273, 2022

PubMed Abstract: 3-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.

PubMed: 35879350
DOI: 10.1038/s41467-022-32025-5

Experimental method

ELECTRON MICROSCOPY (3.33 Å)