Myristoyl's dual role in allosterically regulating and localizing Abl kinase
- Heidelberg Institute for Theoretical Studies, Germany
Abstract
c-Abl kinase, a key signalling hub in many biological processes ranging from cell development to proliferation, is tightly regulated by two inhibitory Src homology domains. An N-terminal myristoyl-modification can bind to a hydrophobic pocket in the kinase C-lobe, which stabilizes the auto-inhibitory assembly. Activation is triggered by myristoyl release. We used molecular dynamics simulations to show how both myristoyl and the Src homology domains are required to impose the full inhibitory effect on the kinase domain, and reveal the allosteric transmission pathway at residue-level resolution. Importantly, we find myristoyl insertion into a membrane to thermodynamically compete with binding to c-Abl. Myristoyl thus not only localizes the protein to the cellular membrane, but membrane attachment at the same time enhances activation of c-Abl by stabilizing its pre-activated state. Our data put forward a model in which lipidation tightly couples kinase localization and regulation, a scheme that currently appears to be unique for this non-receptor tyrosine kinase.
Data availability
Source data for all figures has been deposited on the Dryad Digital Repository under the DOI 10.5061/dryad.9cnp5hqnx
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Data from: Myristoyl's dual role in allosterically regulating and localizing Abl kinaseDryad Digital Repository, doi:10.5061/dryad.9cnp5hqnx.
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft (2082/1 - 390761711)
- Svenja de Buhr
- Frauke Gräter
Klaus Tschira Foundation
- Svenja de Buhr
- Frauke Gräter
bwHPC
- Svenja de Buhr
- Frauke Gräter
Deutsche Forschungsgemeinschaft (INST 35/1134-1 FUGG)
- Svenja de Buhr
- Frauke Gräter
Carl Zeiss Foundation
- Svenja de Buhr
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, de Buhr & Gräter
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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Myristoyl's dual role in allosterically regulating and localizing Abl kinase
eLife 12:e85216.
https://doi.org/10.7554/eLife.85216
