Consensus analysis of Signal Peptide Peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared to Presenilins
Citation:
Friedmann, E., Lemberg, M.K., Weihofen, A., Dev, K.K., Dengler, U., Rovelli, G., Martoglio, B. Consensus analysis of Signal Peptide Peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared to Presenilins, Journal of Biological Chemistry, 2004, 279, 49, 50790-50798Download Item:
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Abstract:
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 four SPP-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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http://people.tcd.ie/devkDescription:
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Author: Dev, Kumlesh
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Journal ArticleCollections:
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J. Biol Chem;279;
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Full text availableKeywords:
Alzheimer’s disease, Preselinins, Intramembrane-cleaving GXGD aspartic proteases, Signal peptide pepti-dase (SPP), SPP-like candidate proteases (SPPLs)Subject (TCD):
NeuroscienceLicences: