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

• Verfasst von: Buhr, Svenja de [VerfasserIn]
• Verfasst von: Gräter, Frauke [VerfasserIn]
• Titel: Myristoyl’s dual role in allosterically regulating and localizing Abl kinase
• Verf.angabe: Svenja de Buhr, Frauke Gräter
• E-Jahr: 2023
• Jahr: 16 October 2023
• Umfang: 17 S.
• Illustrationen: Illustrationen
• Fussnoten: Veröffentlicht: 16. Oktober 2023, Artikelversion: 1. November 2023 ; Gesehen am 27.05.2024
• Titel Quelle: Enthalten in: eLife
• Ort Quelle: Cambridge : eLife Sciences Publications, 2012
• Jahr Quelle: 2023
• Band/Heft Quelle: 12(2023), Artikel-ID e85216, Seite 1-17
• ISSN Quelle: 2050-084X
• DOI: doi:10.7554/eLife.85216
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Abl kinase
• Sach-SW: allostery
• Sach-SW: molecular dynamics simulations
• Sach-SW: myristoyl
• K10plus-PPN: 1889868833

Abstract

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.