Myristoyl's dual role in allosterically regulating and localizing Abl kinase

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.

SEEK ID: https://publications.h-its.org/publications/1556

DOI: 10.7554/eLife.85216

Research Groups: Molecular Biomechanics

Publication type: Journal

Journal: eLife

Publisher: eLife Sciences Publications, Ltd

Citation: eLife 12:e85216.

Date Published: 16th Oct 2023

URL: https://www.biorxiv.org/content/10.1101/2022.12.20.521177v1

Registered Mode: manually

help Submitter
Citation
de Buhr, S., & Gräter, F. (2023). Myristoyl’s dual role in allosterically regulating and localizing Abl kinase. In eLife (Vol. 12). eLife Sciences Publications, Ltd. https://doi.org/10.7554/elife.85216
Activity

Views: 2009

Created: 2nd Jan 2023 at 23:16

Last updated: 5th Mar 2024 at 21:25

help Tags

This item has not yet been tagged.

help Attributions

None

Powered by
(v.1.14.2)
Copyright © 2008 - 2023 The University of Manchester and HITS gGmbH