Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain.
Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain.
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DOI：
10.1038/s41467-022-32025-5
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发表时间：
2022-07-25
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）是胆固醇合成的限速酶，也是降胆固醇他汀类药物的作用靶点。固醇在内质网（ER）膜中的积累加速了HMGCR的降解，减缓了胆固醇的合成。HMGCR的降解通过其与UBIAD 1（含UbiA异戊烯基转移酶结构域的蛋白-1）的结合而受到抑制。这种抑制作用有助于他汀类药物诱导的HMGCR蓄积，从而限制其降胆固醇作用。在这里，我们报告了HMGCR-UBIAD 1复合物的冷冻电子显微镜结构，该复合物通过HMGCR的跨膜螺旋（TM）7和UBIAD 1的TM 2-4之间的相互作用来维持。通过诱变破坏该界面防止复合物形成，增强HMGCR降解。HMGCR的TM 2-6含有一个170个氨基酸的甾醇敏感结构域（SSD），它以两种构象存在，其中一种是降解所必需的。因此，我们的数据支持一种模型，即SSD中TM的重排允许招募引发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。HMG-CoA还原酶（HMGCR）受UBIAD 1和Insigs和β-胆固醇合成的调节。在这里，作者表明HMGCR的甾醇敏感结构域经历构象变化，通过结合其蛋白质调节剂来调节其降解。
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. HMG-CoA reductase (HMGCR) is regulated by UBIAD1 and Insigs and initializes cholesterol synthesis. Here authors show that the sterol sensing domain of HMGCR undergoes conformational changes to regulate its degradation via binding its protein modulators.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
64.5
作者：
Kober DL;Radhakrishnan A;Goldstein JL;Brown MS;Clark LD;Bai XC;Rosenbaum DM
通讯作者：
Rosenbaum DM
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
15.9
作者：
KITA, T;BROWN, MS;GOLDSTEIN, JL
通讯作者：
GOLDSTEIN, JL
影响因子：
15.9
作者：
Engelking, Luke J.;Evers, Bret M.;Liang, Guosheng
通讯作者：
Liang, Guosheng