中文摘要：

3-hydroxy-3-methylglutaryl 辅酶的调整甾醇的降级 reductase (HMGCR ) 是快速的反馈房间由采用控制胆固醇生合成的规章的机制。这个过程被在 HMGCR 和 Insig-1/gp78 之间的导致甾醇的相互作用开始，膜界限 ubiquitin ligase 建筑群。有二 Lys 残余(Lys89 和 Lys248 ) ，在 HMGCR 的膜领域面对 cytosol，并且 Lys248 是主要 ubiquitination 地点。在这研究，我们在 HMGCR 调查了 ubiquitination 地点选择的机制。我们发现到膜的 Lys248 的距离为它的 ubiquitination 是非必需的。然而，邻近在 HMGCR 的 Lys248 的保存 tetra-glutamic 酸残余是必要的。有 tetra 精氨酸的这些否定地控告的残余的代替引起 HMGCR 的抵抗到导致甾醇的 ubiquitination 和降级，这个变异的 HMGCR 罐头仍然绑在 Insig-1 的虽然。我们进一步发现 tetra-glutamic 酸残余为他们的邻近的 Lys 上的修正必要然而并非足够，自从他们不在 HMGCR 或在 SCAP 的 Lys89 上是功能的。UBE2G2， gp78 的以前已知的 E2，被表明涉及 HMGCR 的调整甾醇的 ubiquitination 和降级。在摘要，当在为 ubiquitination 反应的 HMGCR 的一个批评主题由 gp78 和 UBE2G2 调停了，这些结果识别 tetra-glutamic 酸残余。

英文摘要：

Sterol-regulated degradation of 3-hydroxy-3-methylglutaryl eoenzyme A reductase （HMGCR） is a rapid feedback regulatory mechanism by which cells employ to control the cholesterol biosynthesis. This process is initiated by the sterol-induced interaction between HMGCR and Insig-1/ gp78, a membrane-bound ubiquitin figase complex. There are two Lys residues 0Lys89 and Lys248） facing cytosol in the membrane domain of HMGCR, and Lys248 is the major ubiquitination site. In this study, we investigated the mechanism of ubiquitination site selection in HMGCR. We find that the distance of Lys248 to membrane is dispensable for its nbiquitination. However, the conserved tetra-glutamic acid residues adjacent to Lys248 in HMGCR are essential. Replacement of these negatively charged residues with tetraarginine causes the resistance of HMGCR to sterol-induced ubiquitination and degradation, albeit this mutant HMGCR can still binds to Insig-1. We further find that the tetra-glutamic acid residues are necessary but not sufficient for the modification on their adjacent Lys, since they are not functional on Lys89 of HMGCR or in SCAP. UBE2G2, a previously known E2 of gp78, is demonstrated to be involved in the sterol-regulated ubiquitination and degradation of HMGCR. In summary, these results identify the tetraglutamic acid residues as a critical motif in HMGCR for the ubiquitination reaction mediated by gp78 and UBE2G2.