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

Version history

  1. Received: December 3, 2021
  2. Preprint posted: January 10, 2022 (view preprint)
  3. Accepted: May 16, 2022
  4. Accepted Manuscript published: May 17, 2022 (version 1)
  5. Version of Record published: July 14, 2022 (version 2)

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.

Metrics

  • 907
    Page views
  • 212
    Downloads
  • 4
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.76090

Further reading

    1. Biochemistry and Chemical Biology
    Jake W Anderson, David Vaisar ... Natalie G Ahn
    Research Article

    Activation of the extracellular signal-regulated kinase-2 (ERK2) by phosphorylation has been shown to involve changes in protein dynamics, as determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and NMR relaxation dispersion measurements. These can be described by a global exchange between two conformational states of the active kinase, named ‘L’ and ‘R,’ where R is associated with a catalytically productive ATP-binding mode. An ATP-competitive ERK1/2 inhibitor, Vertex-11e, has properties of conformation selection for the R-state, revealing movements of the activation loop that are allosterically coupled to the kinase active site. However, the features of inhibitors important for R-state selection are unknown. Here, we survey a panel of ATP-competitive ERK inhibitors using HDX-MS and NMR and identify 14 new molecules with properties of R-state selection. They reveal effects propagated to distal regions in the P+1 and helix αF segments surrounding the activation loop, as well as helix αL16. Crystal structures of inhibitor complexes with ERK2 reveal systematic shifts in the Gly loop and helix αC, mediated by a Tyr-Tyr ring stacking interaction and the conserved Lys-Glu salt bridge. The findings suggest a model for the R-state involving small movements in the N-lobe that promote compactness within the kinase active site and alter mobility surrounding the activation loop. Such properties of conformation selection might be exploited to modulate the protein docking interface used by ERK substrates and effectors.

    1. Biochemistry and Chemical Biology
    Anne E Hultgren, Nicole MF Patras, Jenna Hicks
    Feature Article

    Organizations that fund research are keen to ensure that their grant selection processes are fair and equitable for all applicants. In 2020, the Arnold and Mabel Beckman Foundation introduced blinding to the first stage of the process used to review applications for Beckman Young Investigator (BYI) awards: applicants were instructed to blind the technical proposal in their initial Letter of Intent by omitting their name, gender, gender-identifying pronouns, and institutional information. Here we examine the impact of this change by comparing the data on gender and institutional prestige of the applicants in the first four years of the new policy (BYI award years 2021–2024) with data on the last four years of the old policy (2017–2020). We find that under the new policy, the distribution of applicants invited to submit a full application shifted from those affiliated with institutions regarded as more prestigious to those outside of this group, and that this trend continued through to the final program awards. We did not find evidence of a shift in the distribution of applicants with respect to gender.