Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins
Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins
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DOI：
10.1074/jbc.m407898200
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发表时间：
2004-12-03
影响因子：
4.8
通讯作者：
Martoglio, B
中科院分区：
文献类型：
--
作者：
Friedmann, E;Lemberg, MK;Martoglio, B
人类基因组编码七种膜内切割 GXGD 天冬氨酸蛋白酶。它们是激活信号分子并与阿尔茨海默病有关的两种早老素、免疫监视所需的信号肽肽酶 (SPP) 和功能未知的四种 SPP 样候选蛋白酶 (SPPL)。在这里，我们描述了 SPP 及其人类同源物 SPPL2a、- 2b、- 2c 和 - 3 的拓扑结构的比较分析。我们证明它们的 N 末端延伸位于细胞外空间，并且除 SPPL3 外，均用 N-聚糖进行修饰。 SPPL2a、-2b 和 -2c 含有信号序列，而 SPP 和 SPPL3 含有 I 型信号锚序列，用于启动蛋白质易位和膜插入。连接含有催化残基的跨膜区域的亲水环面向外质。所有这些蛋白质的 C 末端都暴露在细胞质中。综上所述，我们的研究表明，SPP 及其同系物具有相同的主要结构，具有与早老素相反的方向嵌入膜中的催化结构域。因此，除了早老素之外，SPPL2a、-2b、-2c 和 -3 预计会裂解 II 型导向的底物肽，如原型蛋白酶 SPP。
The human genome encodes seven intramembrane-cleaving GXGD aspartic proteases. These are the two presenilins that activate signaling molecules and are implicated in Alzheimer's disease, signal peptide peptidase (SPP), required for immune surveillance, and fourSPP-like candidate proteases (SPPLs), of unknown function. Here we describe a comparative analysis of the topologies of SPP and its human homologues, SPPL2a, - 2b, - 2c, and - 3. We demonstrate that their N-terminal extensions are located in the extracellular space and, except for SPPL3, are modified with N-glycans. Whereas SPPL2a, - 2b, and - 2c contain a signal sequence, SPP and SPPL3 contain a type I signal anchor sequence for initiation of protein translocation and membrane insertion. The hydrophilic loops joining the transmembrane regions, which contain the catalytic residues, are facing the exoplasm. The C termini of all these proteins are exposed toward the cytosol. Taken together, our study demonstrates that SPP and its homologues are all of the same principal structure with a catalytic domain embedded in the membrane in opposite orientation to that of presenilins. Other than presenilins, SPPL2a, - 2b, - 2c, and - 3 are therefore predicted to cleave type II-oriented substrate peptides like the prototypic protease SPP.