Sampling the conformational space of the catalytic subunit of human γ-secretase

  1. Xiao-chen Bai
  2. Eeson Rajendra
  3. Guanghui Yang
  4. Yigong Shi
  5. Sjors HW Scheres  Is a corresponding author
  1. Medical Research Council, United Kingdom
  2. Tsinghua University, China
  3. Tsinghua university, China

Abstract

Human γ-Secretase is an intra-membrane protease that cleaves many substrates. Aberrant cleavage of Notch is implicated in cancer, while abnormalities in cutting amyloid precursor protein lead to Alzheimer's disease. Our previous cryo-EM structure of γ-secretase revealed considerable disorder in its catalytic subunit presenilin. Here, we describe an image classification procedure that characterizes molecular plasticity at the secondary structure level, and apply this method to identify three distinct conformations in our previous sample. In one of these conformations, an additional transmembrane helix is visible that cannot be attributed to known components of γ-secretase. In addition, we present a γ-secretase structure in complex with the dipeptidic inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). Our results reveal how conformational mobility in the second and sixth transmembrane helices of presenilin is greatly reduced upon binding of DAPT or the additional helix, and form the basis for a new model of how substrate enters the transmembrane domain.

Article and author information

Author details

  1. Xiao-chen Bai

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  2. Eeson Rajendra

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  3. Guanghui Yang

    Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China
    Competing interests
    No competing interests declared.
  4. Yigong Shi

    Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua university, Beijing, China
    Competing interests
    No competing interests declared.
  5. Sjors HW Scheres

    MRC laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    For correspondence
    scheres@mrc-lmb.cam.ac.uk
    Competing interests
    Sjors HW Scheres, Reviewing editor, eLife.

Reviewing Editor

  1. Werner Kühlbrandt, Max Planck Institute of Biophysics, Germany

Version history

  1. Received: August 27, 2015
  2. Accepted: November 30, 2015
  3. Accepted Manuscript published: December 1, 2015 (version 1)
  4. Version of Record published: January 7, 2016 (version 2)

Copyright

© 2015, Bai et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Xiao-chen Bai
  2. Eeson Rajendra
  3. Guanghui Yang
  4. Yigong Shi
  5. Sjors HW Scheres
(2015)
Sampling the conformational space of the catalytic subunit of human γ-secretase
eLife 4:e11182.
https://doi.org/10.7554/eLife.11182

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https://doi.org/10.7554/eLife.11182

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