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HMG CoA还原酶的调节降解需要甾醇传感结构域的构象变化
Nature Communications
(
IF
16.6
)
Pub Date : 2022-07-25
, DOI:
10.1038/s41467-022-32025-5
Hongwen Chen
1
,
Xiaofeng Qi
1
,
Rebecca A Faulkner
1
,
Marc M Schumacher
1
,
Linda M Donnelly
1
,
Russell A DeBose-Boyd
1
,
Xiaochun Li
1,
2
Affiliation
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
3-Hydroxy-3-methylglutaryl coenzyme A 还原酶 (HMGCR) 是胆固醇合成的限速酶,是降胆固醇他汀类药物的靶点。甾醇在内质网 (ER) 膜中的积累加速了 HMGCR 的降解,减缓了胆固醇的合成。HMGCR 的降解受到其与 UBIAD1(含有 UbiA 异戊二烯基转移酶结构域的蛋白 1)的结合的抑制。这种抑制有助于他汀类药物诱导的 HMGCR 积累,从而限制了它们的降胆固醇作用。在这里,我们报告了 HMGCR-UBIAD1 复合物的低温电子显微镜结构,该结构由 HMGCR 的跨膜螺旋 (TM) 7 和 UBIAD1 的 TM 2-4 之间的相互作用维持。通过诱变破坏该界面可防止复合物形成,从而增强 HMGCR 降解。HMGCR 的 TM 2-6 包含一个 170 个氨基酸的甾醇传感结构域 (SSD),它以两种构象存在,其中一种对降解至关重要。因此,我们的数据支持一个模型,即 SSD 中 TM 的重排允许募集启动 HMGCR 降解的蛋白质,这是控制胆固醇合成的调节系统中的关键反应。
"点击查看英文标题和摘要"
Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain
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.
更新日期:2022-07-25