title: Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator.
abstract: γ-Secretase is an intramembrane-cleaving protease responsible for the generation of amyloid-β (Aβ) peptides. Recently, a series of compounds called γ-secretase modulators (GSMs) has been shown to decrease the levels of long toxic Aβ species (i.e., Aβ42), with a concomitant elevation of the production of shorter Aβ species. In this study, we show that a phenylimidazole-type GSM allosterically induces conformational changes in the catalytic site of γ-secretase to augment the proteolytic activity. Analyses using the photoaffinity labeling technique and systematic mutational studies revealed that the phenylimidazole-type GSM targets a previously unidentified extracellular binding pocket within the N-terminal fragment of presenilin (PS). Collectively, we provide a model for the mechanism of action of the phenylimidazole-type GSM in which binding at the luminal side of PS induces a conformational change in the catalytic center of γ-secretase to modulate Aβ production.
authors.affiliation: Departments of Neuropathology and Neuroscience and.
authors.forename: Koji
authors.initials: K
authors.lastname: Takeo
authors.affiliation: Synthetic Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, and.
authors.forename: Shun
authors.initials: S
authors.lastname: Tanimura
authors.affiliation: RIKEN Systems and Structural Biology Center andDivision of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan;
authors.forename: Takehiro
authors.initials: T
authors.lastname: Shinoda
authors.affiliation: Departments of Neuropathology and Neuroscience and.
authors.forename: Satoko
authors.initials: S
authors.lastname: Osawa
authors.affiliation: Synthetic Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, and.
authors.forename: Ivan Krasmirov
authors.initials: IK
authors.lastname: Zahariev
authors.affiliation: Departments of Neuropathology and Neuroscience andFaculty of Medicine, 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.forename: Naoki
authors.initials: N
authors.lastname: Takegami
authors.affiliation: RIKEN Systems and Structural Biology Center andDivision of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan;
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Ishizuka-Katsura
authors.affiliation: RIKEN Systems and Structural Biology Center andDivision of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan;
authors.forename: Naoko
authors.initials: N
authors.lastname: Shinya
authors.affiliation: Departments of Neuropathology and Neuroscience and.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Takagi-Niidome
authors.affiliation: Departments of Neuropathology and Neuroscience and.
authors.forename: Aya
authors.initials: A
authors.lastname: Tominaga
authors.affiliation: RIKEN Systems and Structural Biology Center andDivision of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan;
authors.forename: Noboru
authors.initials: N
authors.lastname: Ohsawa
authors.affiliation: RIKEN Systems and Structural Biology Center andDivision of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan;
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kimura-Someya
authors.affiliation: RIKEN Systems and Structural Biology Center andDivision of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan;
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.affiliation: Synthetic Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, and.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yokoshima
authors.affiliation: RIKEN Systems and Structural Biology Center andRIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan; and.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: Synthetic Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, and.
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukuyama
authors.affiliation: Departments of Neuropathology and Neuroscience andCore Research for Evolutional Science and Technology, Japan Science and Technology Agency, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Departments of Neuropathology and Neuroscience andFaculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000596:Amino Acids / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D004789:Enzyme Activation / Q000187:drug effects; D005453:Fluorescence; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000378:metabolism; D040681:Structural Homology, Protein; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D000596:Amino Acids; D007093:Imidazoles; D010455:Peptides; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; allosteric modulator; amyloid-β protein; chemical biology; intramembrane proteolysis