Active site geometry stabilization of a presenilin homolog by the lipid bilayer promotes intramembrane proteolysis

  1. Lukas P Feilen
  2. Shu-Yu Chen
  3. Akio Fukumori
  4. Regina Feederle
  5. Martin Zacharias
  6. Harald Steiner  Is a corresponding author
  1. German Center for Neurodegenerative Diseases, Germany
  2. Technical University of Munich, Germany
  3. Osaka Medical and Pharmaceutical University, Japan
  4. Helmholtz Zentrum München, Germany
  5. Ludwig-Maximilians-Universität München, Germany

Abstract

Cleavage of membrane proteins in the lipid bilayer by intramembrane proteases is crucial for health and disease. Although different lipid environments can potently modulate their activity, how this is linked to their structural dynamics is unclear. Here we show that the carboxy-peptidase-like activity of the archaeal intramembrane protease PSH, a homolog of the Alzheimer's disease-associated presenilin/γ-secretase is impaired in micelles and promoted in a lipid bilayer. Comparative molecular dynamics simulations revealed that important elements for substrate binding such as transmembrane domain 6a of PSH are more labile in micelles and stabilized in the lipid bilayer. Moreover, consistent with an enhanced interaction of PSH with a transition-state analog inhibitor, the bilayer promoted the formation of the enzyme´s catalytic active site geometry. Our data indicate that the lipid environment of an intramembrane protease plays a critical role in structural stabilization and active site arrangement of the enzyme-substrate complex thereby promoting intramembrane proteolysis.

Data availability

For all figures the source data are provided in the respective source data files. The coordinate and trajectory files of all simulations can be accessed at Zenodo: https://doi.org/10.5281/zenodo.6487373

The following previously published data sets were used

Article and author information

Author details

  1. Lukas P Feilen

    German Center for Neurodegenerative Diseases, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8221-6742
  2. Shu-Yu Chen

    Physics Department T38, Technical University of Munich, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Akio Fukumori

    Department of Pharmacotherapeutics II, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Regina Feederle

    Institute for Diabetes and Obesity, Helmholtz Zentrum München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3981-367X
  5. Martin Zacharias

    Physics Department T38, Technical University of Munich, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Harald Steiner

    Biomedical Center (BMC), Ludwig-Maximilians-Universität München, Munich, Germany
    For correspondence
    harald.steiner@med.uni-muenchen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3935-0318

Funding

Deutsche Forschungsgemeinschaft (263531414 / FOR2290)

  • Martin Zacharias
  • Harald Steiner

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. M Joanne Lemieux, University of Alberta, Canada

Publication history

  1. Received: December 3, 2021
  2. Accepted: May 16, 2022
  3. Accepted Manuscript published: May 17, 2022 (version 1)

Copyright

© 2022, Feilen 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. Lukas P Feilen
  2. Shu-Yu Chen
  3. Akio Fukumori
  4. Regina Feederle
  5. Martin Zacharias
  6. Harald Steiner
(2022)
Active site geometry stabilization of a presenilin homolog by the lipid bilayer promotes intramembrane proteolysis
eLife 11:e76090.
https://doi.org/10.7554/eLife.76090

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