Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
J Biol Chem. 2011 Jul 22;286(29):26188-97. doi: 10.1074/jbc.M111.260273. Epub 2011 Jun 2.
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 Å. Enzymatically active SPP forms a slender, bullet-shaped homotetramer with dimensions of 85 × 85 × 130 Å. 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.
信号肽酶（SPP）是一种非典型的天冬氨酸蛋白酶，可水解底物跨膜结构域内的肽键，并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 SPP 的结构，并重建了分辨率为 22 Å 的三维结构。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 Å。SPP 复合物在菱形侧面上有四个凹面，与分子内部的一个大腔相连。有趣的是，SPP 的 N 端区域足以进行四聚体组装。此外，N 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 的功能单位，其 N 端区域作为结构支架，对 SPP 的跨膜切割活性具有新的调节功能。
