| Autor: |
Shizuka Takagi-Niidome, Tomoki Sasaki, Satoko Osawa, Takeshi Sato, Kanan Morishima, Tetsuo Cai, Takeshi Iwatsubo, Taisuke Tomita |
| Předmět: |
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| Zdroj: |
Journal of Neuroscience; 2/11/2015, Vol. 35 Issue 6, p2646-2656, 11p |
| Abstrakt: |
γ-Secretase is a multisubunit protease complex that is responsible for generating amyloid-ß peptides, which are associated with Alzheimer disease. The catalytic subunit of γ-secretase is presenilin 1 (PS1), which contains an initial substrate-binding site that is distinct from the catalytic site. Processive cleavage is suggested in the intramembrane-cleaving mechanism of γ-secretase. However, it largely remains unknown as to how γ-secretase recognizes its substrate during proteolysis. Here, we identified that the α-helical structural region of hydrophilic loop 1 (HL1) and the C-terminal region of human PS1 are distinct substrate-binding sites. Mutational analyses revealed that substrate binding to the HL1 region is critical for both ε- and γ-cleavage, whereas binding to the C-terminal region hampers γ-cleavage. Moreover, we propose that substrate binding triggers conformational changes in PS1, rendering it suitable for catalysis. Our data provide new insights into the complicated catalytic mechanism of PS1. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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