The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility.
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.
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Allan Joaquim
AJ
Lamontanara
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Sandrine
S
Georgeon
European Molecular Biology Laboratory, Hamburg Outstation, 22603 Hamburg, Germany.
Giancarlo
G
Tria
European Molecular Biology Laboratory, Hamburg Outstation, 22603 Hamburg, Germany.
Dmitri I
DI
Svergun
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.
Oliver
O
Hantschel
D004789:Enzyme Activation / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000502:physiology; D016374:Oncogene Proteins v-abl / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051562:Proto-Oncogene Proteins c-bcr / Q000502:physiology; D018909:src Homology Domains / Q000502:physiology*
D016374:Oncogene Proteins v-abl; D016044:Fusion Proteins, bcr-abl; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr