Scap structures highlight key role for rotation of intertwined luminal loops in cholesterol sensing.
Scap structures highlight key role for rotation of intertwined luminal loops in cholesterol sensing.
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DOI：
10.1016/j.cell.2021.05.019
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发表时间：
2021-07-08
期刊：
影响因子：
64.5
通讯作者：
Rosenbaum DM
中科院分区：
文献类型：
--
作者：
Kober DL;Radhakrishnan A;Goldstein JL;Brown MS;Clark LD;Bai XC;Rosenbaum DM
胆固醇敏感蛋白Scap通过将被称为SREBP的膜结合转录因子从ER转运到高尔基体进行蛋白水解激活来诱导胆固醇合成。转运需要Scap的两个ER管腔环（L1和L7）之间的相互作用，这两个环位于膜内固醇敏感结构域（SSD）的侧翼。胆固醇通过与L1结合来抑制Scap转运，L1触发Scap与ER滞留蛋白Insig结合。在这里，我们使用cryo-EM来阐明全长鸡Scap的两种结构：i）不含Insig的野生型;和ii）与不含胆固醇的鸡Insig结合的突变体Scap。引人注目的是，L1和L7紧密交错形成一个球状结构域，作为连接SSD和Scap其余部分的管腔平台。在Insig的存在下，该平台经历伴随Scap的跨膜螺旋重排的大旋转。我们推测，这种构象变化停止Scap运输SREBP和抑制胆固醇合成。可视化的Scap，胆固醇传感器，调节细胞内定位的SREBP，在复杂的Inisg牵连运动的胆固醇相互作用域巡逻近端膜区域的甾醇。
The cholesterol-sensing protein Scap induces cholesterol synthesis by transporting membrane-bound transcription factors called SREBPs from ER to Golgi for proteolytic activation. Transport requires interaction between Scap’s two ER luminal loops (L1 and L7) that flank an intramembrane sterol-sensing domain (SSD). Cholesterol inhibits Scap transport by binding to L1, which triggers Scap’s binding to Insig, an ER retention protein. Here, we used cryo-EM to elucidate two structures of full-length chicken Scap: i) wild-type free of Insigs; and ii) mutant Scap bound to chicken Insig without cholesterol. Strikingly, L1 and L7 intertwine tightly to form a globular domain that acts as a luminal platform connecting the SSD to the rest of Scap. In the presence of Insig, this platform undergoes a large rotation accompanied by rearrangement of Scap’s transmembrane helices. We postulate that this conformational change halts Scap transport of SREBPs and inhibits cholesterol synthesis. Visualization of Scap, the cholesterol sensor that modulates intracellular localization of SREBP, in complex with Inisg implicates movement of a cholesterol-interacting domain in patrolling proximal membrane regions for sterols.
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DOI：
10.1073/pnas.2018578117
发表时间：
2020-11-10
影响因子：
11.1
作者：
Kober, Daniel L.;Xu, Shimeng;Radhakrishnan, Arun
通讯作者：
Radhakrishnan, Arun
影响因子：
4.8
作者：
Infante, Rodney E.;Abi-Mosleh, Lina;Goldstein, Joseph L.
通讯作者：
Goldstein, Joseph L.
影响因子：
7.7
作者：
Bai, Xiao-chen;Rajendra, Eeson;Scheres, Sjors H. W.
通讯作者：
Scheres, Sjors H. W.
DOI：
10.1073/pnas.0500206102
发表时间：
2005-03-01
影响因子：
11.1
作者：
Feramisco, JD;Radhakrishnan, A;Goldstein, JL
通讯作者：
Goldstein, JL
影响因子：
--
作者：
Giudicelli, Veronique;Brochet, Xavier;Lefranc, Marie-Paule
通讯作者：
Lefranc, Marie-Paule