Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases

Abstract

The V617F mutation in the Jak2 pseudokinase domain causes myeloproliferative neoplasms, and the equivalent mutation in Jak1 (V658F) is found in T-cell leukemias. Crystal structures of wild-type and V658F-mutant human Jak1 pseudokinase reveal a conformational switch that remodels a linker segment encoded by exon 12, which is also a site of mutations in Jak2. This switch is required for V617F-mediated Jak2 activation and possibly for physiologic Jak activation.

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Figure 1: Structure of the Jak1 pseudokinase domain.
Figure 2: Crystal structure of the V658F-mutant Jak1 pseudokinase domain.

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Acknowledgements

We thank beamline personnel at the Macromolecular Crystallography Resource at the Cornell High Energy Synchrotron Source (MacCHESS) and the Northeast Collaborative Access Team at the Advanced Photon Source, Argonne National Laboratory (NE-CAT) for assistance with data collection and processing. We thank K. Arnett for generous help with Jak1 autophosphorylation experiments. MacCHESS and NE-CAT are supported by grants from the US National Institutes of Health (NIH). This work was supported in part by NIH grant CA134660 (M.S.) and NIH training grants GM008313 (J.M.R.) and CA936132 (R.M.), and by funding from Novartis Institutes for Biomedical Research (M.J.E.).

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Contributions

A.V.T., A.D., R.M. and J.M.R. designed and performed experiments and analyzed data. Y.J. carried out experiments. S.M.G. and C.U.K. contributed pressure cryocooling, and S.B.F. and J.A.M. contributed MS analysis. A.V.T., R.M., M.S., J.D.G. and M.J.E. designed experiments, analyzed data, and wrote the manuscript.

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Correspondence to Michael J Eck.

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Competing interests

J.D.G. and M.J.E. are consultants for and receive research support from Novartis Institutes for Biomedical Research.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Table 1 (PDF 2312 kb)

Supplementary Data Set 1

Consurf alignment (PDF 1856 kb)

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Toms, A., Deshpande, A., McNally, R. et al. Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases. Nat Struct Mol Biol 20, 1221–1223 (2013). https://doi.org/10.1038/nsmb.2673

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