title: Cooperative roles of hydrophilic loop 1 and the C-terminus of presenilin 1 in the substrate-gating mechanism of γ-secretase.
abstract: 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.
authors: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Shizuka
authors: S
authors: Takagi-Niidome
authors: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Tomoki
authors: T
authors: Sasaki
authors: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Satoko
authors: S
authors: Osawa
authors: Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Takeshi
authors: T
authors: Sato
authors: Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and.
authors: Kanan
authors: K
authors: Morishima
authors: Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and.
authors: Tetsuo
authors: T
authors: Cai
authors: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Takeshi
authors: T
authors: Iwatsubo
authors: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, taisuke@mol.f.u-tokyo.ac.jp.
authors: Taisuke
authors: http://orcid.org/0000-0002-0075-5943
authors: T
authors: Tomita
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053764:Presenilin-1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017433:Protein Structure, Secondary; D013379:Substrate Specificity; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer; amyloid; enzyme; intramembrane; protease; selectivity