A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood
A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood
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DOI：
10.1073/pnas.96.20.11041
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发表时间：
1999-09-28
影响因子：
11.1
通讯作者：
Goldstein, JL
中科院分区：
文献类型：
--
作者：
Brown, MS;Goldstein, JL
细胞膜的完整性是由磷脂中胆固醇与不饱和和饱和脂肪酸之间的平衡来维持的，这种平衡是由称为类固醇调节元件结合蛋白(SREBPs)的膜结合转录因子维持的，这种转录因子激活编码胆固醇和脂肪酸生物合成的酶的基因。为了促进转录，SREBPs的活性NH2末端结构域通过两次连续的切割从内质网膜中释放出来。第一个是由Site-1蛋白酶(SLP)催化的，SLP是一种膜结合的枯草杆菌相关丝氨酸蛋白酶，它裂解SREBP的亲水性环，投射到内质网腔。位于-2位的第二次切割需要S2P的作用，S2P是一种疏水蛋白，似乎是一种锌金属蛋白酶。这种切割是不寻常的，因为它发生在SREBP的跨膜结构域中，甾醇通过抑制SLP来阻止SREBP的加工。这种反应是由SREBP裂解激活蛋白(SCAP)介导的，SREBP裂解激活蛋白是一种调节蛋白，激活S1P，同时也是一种类固醇传感器，当类固醇在细胞中过度积累时，它就会失去活性。这些受调控的蛋白分解反应最终负责控制膜、细胞和血液中的胆固醇水平。
The integrity of cell membranes is maintained by a balance between the amount of cholesterol and the amounts of unsaturated and saturated fatty acids in phospholipids, This balance is maintained by membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) that activate genes encoding enzymes of cholesterol and fatty acid biosynthesis. To enhance transcription, the active NH2-terminal domains of SREBPs are released from endoplasmic reticulum membranes by two sequential cleavages. The first is catalyzed by Site-1 protease (SLP), a membrane-bound subtilisin-related serine protease that cleaves the hydrophilic loop of SREBP that projects into the endoplasmic reticulum lumen. The second cleavage, at Site-2, requires the action of S2P, a hydrophobic protein that appears to be a zinc metalloprotease. This cleavage is unusual because it occurs within a membrane-spanning domain of SREBP, Sterols block SREBP processing by inhibiting SLP. This response is mediated by SREBP cleavage-activating protein (SCAP), a regulatory protein that activates S1P and also serves as a sterol sensor, losing its activity when sterols overaccumulate in cells. These regulated proteolytic cleavage reactions are ultimately responsible for controlling the level of cholesterol in membranes, cells, and blood.