Identifizierung von Substratbindestellen in der γ-Sekretase

Abstract

The lack of detailed information on the interactions between substrates and enzymes is a major gap in understanding the mechanisms of many proteases. Using the Alzheimer’s disease protease γ-secretase as an example, we show how a previously developed versatile chemical biology approach allows to systematically identify molecular interactions with the enzyme at the amino acid level of the substrate. Furthermore, this approach provides additional mechanistic insights that could also aid in the development of advanced drugs against this key protease.

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Literatur

  1. [1]

    Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. [2]

    Bursavich MG, Harrison BA, Blain JF (2016) Gamma secretase modulators: new Alzheimer’s drugs on the horizon? J Med Chem 59:7389–7409

    CAS  Article  PubMed  Google Scholar 

  3. [3]

    Sun L, Li X, Shi Y (2016) Structural biology of intramembrane proteases: mechanistic insights from rhomboid and S2P to γ-secretase. Curr Opin Struct Biol 37:97–107

    CAS  Article  PubMed  Google Scholar 

  4. [4]

    Bai XC, Yan C, Yang G et al. (2015) An atomic structure of human γ-secretase. Nature 525:212–217

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. [5]

    Fukumori A, Steiner H (2016) Substrate recruitment of γ-secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping. EMBO J 35:1628–1643

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. [6]

    Chin JW, Martin AB, King DS et al. (2002) Addition of a photocrosslinking amino acid to the genetic code of Escherichia coli. Proc Natl Acad Sci USA 99:11020–11024

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Harald Steiner.

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Akio Fukumori Medizinstudium an der Universität Osaka in Japan und Facharzt für Psychiatrie. Tätigkeiten als Postdoktorand an der LMU München und als Seniorwissenschaftler am Deutschen Zentrum für Neurodegenerative Erkrankungen (DZNE), München. 2016 Rückkehr nach Japan. Dort Gruppenleiter am National Center for Geriatrics and Gerontology (NCGG) in Obu und Visiting Associate Professor an der Universität Osaka.

Johannes Trambauer Biochemiestudium an der Universität Tübingen. Seit 2013 Doktorand an der LMU München.

Lukas P. Feilen Studium der Molekularen Biotechnologie an der Universität Heidelberg. Seit 2016 Doktorand am Deutschen Zentrum für Neurodegenerative Erkrankungen (DZNE), München.

Harald Steiner Chemiestudium an der Universität Stuttgart. Promotion in Biochemie an der LMU München. Nach Postdoktorandentätigkeit an der Universität Heidelberg am Zentralinstitut für Seelische Gesundheit in Mannheim seit 1999 Gruppenleiter an der LMU München, dort seit 2007 apl. Professor für Biochemie. 2013 Ernennung zum akademischen Direktor.

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Fukumori, A., Trambauer, J., Feilen, L.P. et al. Identifizierung von Substratbindestellen in der γ-Sekretase. Biospektrum 24, 34–36 (2018). https://doi.org/10.1007/s12268-018-0888-7

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