2007 Fiscal Year Final Research Report Summary
Molecular analysis of intramembrane proteolysis by combinatorial reconstitution and chemical genetics of membrane protein complex.
| Project/Area Number |
17390015
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | The University of Tokyo |
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Principal Investigator |
TOMITA Taisuke The University of Tokyo, Graduate School of Pharmaceutical Sciences, Associate professor (30292957)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Alzheimer's disease / Secretase / Amyloid / Intramembrane proteolysis |
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| Research Abstract |
Several lines of evidence suggest that aggregation and deposition of amyloid-β peptide (Aβ) are involved in the pathogenesis of Alzheimer's dipease, that is the most common cause of dementia with aging. Thus, γ-secretase, that is a pivotal enzyme in generating Aβ, is a plausible therapeutic target for AD. However, as γ-secretase is an atypical protease and endoproteolyzes a scissile bond within the hydrophobic lipid bilayer, the mode of action whereby γ-secretase cleaves its substrate still remains unknown. To elucidate the molecular mechanism of γ-secretase mediated cleavage for the development of AD therapeutics, we have extensively analyzed recombinant γ-secretase complex reconstituted by mammalian and insect ?cell expression systems. Moreover, through world-wide collaborations, we have investigated γ-secretase by structural and chemical biological approaches. Finally, we have proposed the "catalytic pore" model for intramembrane proteolysis by γ-secretage. We found that the intramembrane-cleaving reaction takes place within this pore, and can be regulated by the pharmacological and genetic modulation of the catalytic pore structure. Moreover, we analyzed the physiological function of γ-secreta se to prove that the functional modulation of γ-secretase activity is plausible therapeutics for AD. To this end, we characterized the stmcture of γ-secretape complex by single particle analysis. Further extensive efforts for the understanding the molecular mechanism of γ-secretase may contribute to the development of promising therapeutics using safe bioavailable compounds for AD.
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Research Products
(59 results)
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[Journal Article] Three-dimensional structure of the y-secretase complex.2006
Author(s)
Ogura T, Mio K, Hayashi I, Miyashita H, Fukuda R, Kopan R, Kodama T, Hamakubo T, Iwatsubo T, Tomita T, Sato C
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Journal Title
Biochem Biophys Res Comm 343
Pages: 525-534
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] C-terminal fragment of Presenilin is the molecular target of a dipeptidic γ-secretase-specific Inhibitor DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycinet-Butyl Ester).2006
Author(s)
Morohashi Y, Kan T, Tominari Y, Fuwa H, Okamura Y, Watanabe N, Sato C, Natsugari H, Fukuyama T, Iwatsubo T, Tomita T
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Journal Title
J Biol Chem 281
Pages: 14670-14676
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Novel γ-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates.2006
Author(s)
Takahashi Y, Fuwa H, Kaneko A, Sasaki M, Yokoshima S, Koizumi H, Takebe T, Kan T, Iwatsubo T, Tomita T, Natsugari H, Fukuyama T
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Journal Title
Bioorg Med Chem Lett 16
Pages: 3813-3816
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Naphthyl and coumarinyl biarylpiperazine derivatives as highly potent human β-secretase inhibitors. Design, synthesis, enzymatic BACE-1 and cell assays.2006
Author(s)
Garino C, Tomita T, Pietrancosta N, Laras Y, Rosas R, Herbette G, Maigret B, Quelever G, Iwatsubo T, Kraus J.-L
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Journal Title
J Med Chem 49
Pages: 4275-4285
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling.2005
Author(s)
Takeda T, Asahi M, Yamaguchi O, Hikoso S, Nakayama H, Kusakari Y, Kawai M, Hongo K, Higuchi Y, Kashiwase K, Watanabe T, Taniike M, Nakai A, Nishida K, Kurihara S, Donoviel DB, Bernstein A, Tomita T, Iwatsubo T, Hori M, Otsu K
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Journal Title
FASEB J. 19
Pages: 2069-2071
Description
「研究成果報告書概要(欧文)」より
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