Myristoyl's dual role in allosterically regulating and localizing Abl kinase.
| Autor: | de Buhr S; Heidelberg Institute for Theoretical Studies (HITS), Heidelberg University, Heidelberg, Germany., Gräter F; Heidelberg Institute for Theoretical Studies (HITS), Heidelberg University, Heidelberg, Germany.; Institute for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany. |
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| Jazyk: | angličtina |
| Zdroj: | ELife [Elife] 2023 Oct 16; Vol. 12. Date of Electronic Publication: 2023 Oct 16. |
| DOI: | 10.7554/eLife.85216 |
| Abstrakt: | c-Abl kinase, a key signaling 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 autoinhibitory 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 preactivated 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. Competing Interests: Sd, FG No competing interests declared (© 2023, de Buhr and Gräter.) |
| Databáze: | MEDLINE |
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