JAK (Janus kinase) 2 plays a critical role in signal transduction through several cytokine receptors. JAKs contain a typical tyrosine kinase domain preceded by a pseudokinase [JH2 (JAK homology 2)] domain which has been considered to be catalytically inactive. Identification of activating mutations in the JH2 domain of JAK2 as the major cause for polycythaemia vera and other MPNs (myeloproliferative neoplasms) demonstrate the critical regulatory function for this domain, but the underlying mechanisms have remained elusive. We have performed biochemical and functional analysis on the JH2 domain of JAK2. The results indicate that JH2 functions as an active protein kinase and phosphorylates two residues in JAK2 (Ser523 and Tyr570) that have been shown previously to be negative regulatory sites for JAK2 activity. The crystal structure of the JAK2 JH2 domain provides an explanation for the functional findings and shows that JH2 adopts a prototypical kinase fold, but binds MgATP through a non-canonical mode. The structure of the most prevalent pathogenic JH2 mutation V617F shows a high level of similarity to wild-type JH2. The most notable structural deviation is observed in the N-lobe αC-helix. The structural and biochemical data together with MD (molecular dynamics) simulations show that the V617F mutation rigidifies the αC-helix, which results in hyperactivation of the JH1 domain through an as yet unidentified mechanism. These results provide structural and functional insights into the normal and pathogenic function of the JH2 domain of JAK2.
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Conference Article|
July 18 2013
New insights into the structure and function of the pseudokinase domain in JAK2
Olli Silvennoinen;
Olli Silvennoinen
1
*School of Medicine and Institute of Biomedical Technology, University of Tampere, 33014 Tampere, Finland
†Department of Internal Medicine, Tampere University Hospital, 33520 Tampere, Finland
1Correspondence may be addressed to either of these authors (emailolli.silvennoinen@uta.fi or Stevan.Hubbard@med.nyu.edu).
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Daniela Ungureanu;
Daniela Ungureanu
*School of Medicine and Institute of Biomedical Technology, University of Tampere, 33014 Tampere, Finland
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Yashavanthi Niranjan;
Yashavanthi Niranjan
*School of Medicine and Institute of Biomedical Technology, University of Tampere, 33014 Tampere, Finland
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Henrik Hammaren;
Henrik Hammaren
*School of Medicine and Institute of Biomedical Technology, University of Tampere, 33014 Tampere, Finland
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Rajintha Bandaranayake;
Rajintha Bandaranayake
‡Structural Biology Program, Kimmel Center for Biology and Medicine of the Skirball Institute, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, U.S.A.
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Stevan R. Hubbard
Stevan R. Hubbard
1
‡Structural Biology Program, Kimmel Center for Biology and Medicine of the Skirball Institute, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, U.S.A.
1Correspondence may be addressed to either of these authors (emailolli.silvennoinen@uta.fi or Stevan.Hubbard@med.nyu.edu).
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Publisher: Portland Press Ltd
Received:
April 30 2013
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem Soc Trans (2013) 41 (4): 1002–1007.
Article history
Received:
April 30 2013
Citation
Olli Silvennoinen, Daniela Ungureanu, Yashavanthi Niranjan, Henrik Hammaren, Rajintha Bandaranayake, Stevan R. Hubbard; New insights into the structure and function of the pseudokinase domain in JAK2. Biochem Soc Trans 1 August 2013; 41 (4): 1002–1007. doi: https://doi.org/10.1042/BST20130005
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