The inhibition of degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by sterol regulatory element binding protein cleavage-activating protein requires four phenylalanine residues in span 6 of HMG-CoA reductase transmembrane domain
The inhibition of degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by sterol regulatory element binding protein cleavage-activating protein requires four phenylalanine residues in span 6 of HMG-CoA reductase transmembrane domain
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DOI：
10.1016/s0003-9861(03)00168-1
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发表时间：
2003-06-15
影响因子：
3.9
通讯作者：
Simoni, RD
中科院分区：
文献类型：
--
作者：
Xu, LW;Simoni, RD
3-羟基-3-甲基戊二酰辅酶A还原酶（HMGR）是胆固醇生物合成途径中的限速酶。这种内质网膜蛋白含有一个胞质催化结构域和一个跨膜结构域，该跨膜结构域具有八个膜跨度，这是甾醇加速降解所必需的。竞争实验表明，野生型跨膜结构域的HMGR和甾醇调节元件结合蛋白裂解激活蛋白（SCAP）阻止完整的HMGR和HMGal，模型蛋白含有HMGR的膜结构域连接到大肠杆菌β-半乳糖苷酶的甾醇加速降解。然而，突变体的跨膜结构域的HMGR和SCAP的甾醇敏感功能被废除不抑制甾醇加速降解的HMGR和HMGal。此外，我们对HMGal的诱变研究表明，HMGR的span 6中保守的4个Phe残基和其他甾醇相关蛋白的甾醇敏感结构域是HMGR调节降解所必需的。这些结果表明，HMGR和SCAP竞争结合的甾醇调节调节蛋白，这种结合可能需要四个苯丙氨酸残基。(C)2003 Elsevier Science（美国）。All rights reserved.
3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme in the cholesterol biosynthetic pathway. This endoplasmic reticulum membrane protein contains a cytosolic catalytic domain and a transmembrane domain with eight membrane spans that are necessary for sterol-accelerated degradation. Competition experiments showed that wild-type transmembrane domains of HMGR and sterol regulatory element binding protein cleavage-activating protein (SCAP) blocked sterol-accelerated degradation of intact HMGR and HMGal, a model protein containing the membrane domain of HMGR linked to Escherichia coli beta-galactosidase. However, mutant transmembrane domains of HMGR and SCAP whose sterol-sensing functions were abolished did not inhibit sterol-accelerated degradation of HMGR and HMGal. In addition, our mutagenesis studies on HMGal indicated that four Phe residues conserved in span 6 of HMGR and the sterol-sensing domains of other sterol-related proteins are required for the regulated degradation of HMGR. These results suggest that HMGR and SCAP compete for binding to a sterol-regulated regulator protein, and this binding may need the four Phe residues. (C) 2003 Elsevier Science (USA). All rights reserved.