Functional Analysis of the Transmembrane Domains of Presenilin 1

γ-Secretase is a multimeric membrane protein complex composed of presenilin (PS), nicastrin, Aph-1, and Pen-2, which mediates intramembrane proteolysis of a range of type I transmembrane proteins. We previously analyzed the functional roles of the N-terminal transmembrane domains (TMDs) 1–6 of PS1 i...

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Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 285; no. 26; pp. 19738 - 19746
Main Authors:	Watanabe 渡邊直登, Naoto, Takagi 高木穏香, Shizuka, Tominaga 富永綾, Aya, Tomita 富田泰輔, Taisuke, Iwatsubo 岩坪威, Takeshi
Format:	Journal Article
Language:	English
Published:	Elsevier Inc 01-06-2010
Subjects:	Alzheimers Disease Amyloid Aspartic Protease Membrane Enzymes Presenilin Secretases Presenilin Amyloid Membrane Enzymes Secretases Aspartic Protease Alzheimers Disease
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Summary:	γ-Secretase is a multimeric membrane protein complex composed of presenilin (PS), nicastrin, Aph-1, and Pen-2, which mediates intramembrane proteolysis of a range of type I transmembrane proteins. We previously analyzed the functional roles of the N-terminal transmembrane domains (TMDs) 1–6 of PS1 in the assembly and proteolytic activity of the γ-secretase using a series of TMD-swap PS1 mutants. Here we applied the TMD-swap method to all the TMDs of PS1 for the structure-function analysis of the proteolytic mechanism of γ-secretase. We found that TMD2- or -6-swapped mutant PS1 failed to bind the helical peptide-based, substrate-mimic γ-secretase inhibitor. Cross-linking experiments revealed that both TMD2 and TMD6 of PS1 locate in proximity to the TMD9, the latter being implicated in the initial substrate binding. Taken together, our data suggest that TMD2 and the luminal side of TMD6 are involved in the formation of the initial substrate-binding site of the γ-secretase complex.
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M110.101287