Three-dimensional Structure of the Signal Peptide Peptidase
Three-dimensional Structure of the Signal Peptide Peptidase
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DOI：
10.1074/jbc.m111.260273
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发表时间：
2011-07-22
影响因子：
4.8
通讯作者：
Iwatsubo, Takeshi
中科院分区：
文献类型：
--
作者：
Miyashita, Hiroyuki;Maruyama, Yuusuke;Iwatsubo, Takeshi
信号肽肽酶（SPP）是一种非典型的天冬氨酸蛋白酶，其水解底物的跨膜结构域内的肽键，并且涉及多种生物学和病理学功能。在这里，我们通过电子显微镜分析了人类SPP的结构，并以22埃的分辨率重建了三维结构。具有酶活性的SPP形成细长的子弹形同源四聚体，尺寸为85 × 85 × 130埃。SPP复合物在菱形的侧面有四个凹面，连接到分子内部的一个大腔室。有趣的是，SPP的N-末端区域足以进行四聚体组装。此外，N-末端区域的过表达抑制了内源性SPP四聚体的形成和细胞内的蛋白水解活性。这些数据表明同源四聚体是SPP的功能单元，其N-末端区域作为结构支架，对SPP的膜内切割活性具有新的调节功能。
Signal peptide peptidase (SPP) is an atypical aspartic protease that hydrolyzes peptide bonds within the transmembrane domain of substrates and is implicated in several biological and pathological functions. Here, we analyzed the structure of human SPP by electron microscopy and reconstructed the three-dimensional structure at a resolution of 22 angstrom. Enzymatically active SPP forms a slender, bullet-shaped homotetramer with dimensions of 85 x 85 x 130 angstrom. The SPP complex has four concaves on the rhombus-like sides, connected to a large chamber inside the molecule. Intriguingly, the N-terminal region of SPP is sufficient for the tetrameric assembly. Moreover, overexpression of the N-terminal region inhibited the formation of the endogenous SPP tetramer and the proteolytic activity within cells. These data suggest that the homotetramer is the functional unit of SPP and that its N-terminal region, which works as the structural scaffold, has a novel modulatory function for the intramembrane-cleaving activity of SPP.