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Nat Struct Mol Biol. 2014 Jul;21(7):579-84. doi: 10.1038/nsmb.2849. Epub 2014 Jun 11.

Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase.

Author information

1
1] D. E. Shaw Research, New York, New York, USA. [2].
2
1] Kimmel Center for Biology and Medicine of the Skirball Institute, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA. [2].
3
School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland.
4
D. E. Shaw Research, New York, New York, USA.
5
Systems Immunology Laboratory, Immunology Frontier Research Center, Osaka University, Suita, Japan.
6
1] D. E. Shaw Research, New York, New York, USA. [2] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA.
7
Kimmel Center for Biology and Medicine of the Skirball Institute, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.

Abstract

Janus kinase-2 (JAK2) mediates signaling by various cytokines, including erythropoietin and growth hormone. JAK2 possesses tandem pseudokinase and tyrosine-kinase domains. Mutations in the pseudokinase domain are causally linked to myeloproliferative neoplasms (MPNs) in humans. The structure of the JAK2 tandem kinase domains is unknown, and therefore the molecular bases for pseudokinase-mediated autoinhibition and pathogenic activation remain obscure. Using molecular dynamics simulations of protein-protein docking, we produced a structural model for the autoinhibitory interaction between the JAK2 pseudokinase and kinase domains. A striking feature of our model, which is supported by mutagenesis experiments, is that nearly all of the disease mutations map to the domain interface. The simulations indicate that the kinase domain is stabilized in an inactive state by the pseudokinase domain, and they offer a molecular rationale for the hyperactivity of V617F, the predominant JAK2 MPN mutation.

PMID:
24918548
PMCID:
PMC4508010
DOI:
10.1038/nsmb.2849
[Indexed for MEDLINE]
Free PMC Article

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