Cooperative Roles of Hydrophilic Loop 1 and the C-Terminus of Presenilin 1 in the Substrate-Gating Mechanism of γ-Secretase
| Autor: | Tetsuo Cai, Satoko Osawa, Takeshi Iwatsubo, Taisuke Tomita, Shizuka Takagi-Niidome, Takeshi Sato, Kanan Morishima, Tomoki Sasaki |
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| Rok vydání: | 2015 |
| Předmět: |
Proteolysis
Protein subunit medicine.medical_treatment Molecular Sequence Data Gating Biology Transfection Cleavage (embryo) Protein Structure Secondary Presenilin Substrate Specificity Amyloid beta-Protein Precursor Mice mental disorders Presenilin-1 medicine Animals Humans Amino Acid Sequence Mice Knockout chemistry.chemical_classification Protease medicine.diagnostic_test General Neuroscience C-terminus Articles Enzyme chemistry Biochemistry Biophysics Amyloid Precursor Protein Secretases |
| Zdroj: | The Journal of Neuroscience. 35:2646-2656 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | γ-Secretase is a multisubunit protease complex that is responsible for generating amyloid-β 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. |
| Databáze: | OpenAIRE |
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