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Nat Commun. 2014 Nov 17;5:5470. doi: 10.1038/ncomms6470.

The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility.

Author information

1
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
2
European Molecular Biology Laboratory, Hamburg Outstation, 22603 Hamburg, Germany.
3
1] Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland [2] ISREC Foundation Chair in Translational Oncology, Lausanne, Switzerland.

Abstract

The activity of protein kinases is regulated by multiple molecular mechanisms, and their disruption is a common driver of oncogenesis. A central and almost universal control element of protein kinase activity is the activation loop that utilizes both conformation and phosphorylation status to determine substrate access. In this study, we use recombinant Abl tyrosine kinases and conformation-specific kinase inhibitors to quantitatively analyse structural changes that occur after Abl activation. Allosteric SH2-kinase domain interactions were previously shown to be essential for the leukemogenesis caused by the Bcr-Abl oncoprotein. We find that these allosteric interactions switch the Abl activation loop from a closed to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker. Disruption of the SH2-kinase interaction abolishes activation loop phosphorylation. Our analysis provides a molecular mechanism for the SH2 domain-dependent activation of Abl that may also regulate other tyrosine kinases.

PMID:
25399951
DOI:
10.1038/ncomms6470
[Indexed for MEDLINE]

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