TY - JOUR
T1 - Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain
AU - Chen, Hongwen
AU - Qi, Xiaofeng
AU - Faulkner, Rebecca A.
AU - Schumacher, Marc M.
AU - Donnelly, Linda M.
AU - DeBose-Boyd, Russell A.
AU - Li, Xiaochun
N1 - Funding Information:
We thank D. Stoddard at the UT Southwestern Cryo-EM Facility (funded in part by the CPRIT Core Facility Support Award RP170644) for data collection, L. Beatty for help with tissue culture and M. Brown, J. Goldstein for discussion during manuscript preparation. We thank A. Kossiakoff and S. Mukherjee for providing the plasmid for anti-BRIL Fab expression. This work was supported by the Endowed Scholars Program in Medical Science of UT Southwestern Medical Center, Welch Foundation (I-1957, to X.L.) and NIH grant P01 HL160487, P01 HL020948, R01 GM134700 (to R.D.B. and X.L.). X.Q. is a recipient of DDBrown Fellowship of Life Sciences Research Foundation. X.L. is a Damon Runyon-Rachleff Innovator supported by the Damon Runyon Cancer Research Foundation (DRR-53S-19) and a Rita C. and William P. Clements Jr. Scholar in Biomedical Research at UT Southwestern Medical Center.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-32025-5
DO - 10.1038/s41467-022-32025-5
M3 - Article
C2 - 35879350
AN - SCOPUS:85134744092
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4273
ER -