Active site geometry stabilization of a presenilin homolog by the lipid bilayer promotes intramembrane proteolysis
- German Center for Neurodegenerative Diseases, Germany
- Technical University of Munich, Germany
- Osaka Medical and Pharmaceutical University, Japan
- Helmholtz Zentrum München, Germany
- 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
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Recognition of the amyloid precursor protein by human γ-secretaseRCSB Protein Data Bank, 6IYC.
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Structure of a presenilin family intramembrane aspartate proteaseRCSB Protein Data Bank, 4HYG.
Article and author information
Author details
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.
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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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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