Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins

被引:84
作者
Friedmann, E
Lemberg, MK
Weihofen, A
Dev, KK
Dengler, U
Rovelli, G
Martoglio, B [1 ]
机构
[1] ETH Honggerberg, Swiss Fed Inst Technol, Inst Biochem, CH-8093 Zurich, Switzerland
[2] Novartis Pharma AG, Nervous Syst Res, Novartis Inst Biomed Res, CH-4002 Basel, Switzerland
[3] Novartis Pharma AG, Funct Gen, Novartis Inst Biomed Res, CH-4002 Basel, Switzerland
关键词
D O I
10.1074/jbc.M407898200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:50790 / 50798
页数:9
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