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

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

Nature communications (2014-11-18)
Allan Joaquim Lamontanara, Sandrine Georgeon, Giancarlo Tria, Dmitri I Svergun, Oliver Hantschel
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.

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