Document Detail


Regulation of JAK2 Activation by Janus Homology 2: Evidence from Molecular Dynamics Simulations.
MedLine Citation:
PMID:  23033920     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Janus kinase 2 (JAK2) is a protein tyrosine kinase implicated in signalling by specific members of the cytokine receptor family. Although it has been established that the JAK2 tyrosine kinase is negatively regulated by the JAK homology 2 (JH2) pseudokinase domain, the underlying mechanism of JH2 mediated regulation remains elusive. To elucidate the regulation of JAK2 kinase, we have built a structural model for the kinase and pseudokinase domains of JAK2. An asymmetric dimer is proposed, in which the kinase domain JH1 occupies a position where it could not be activated. We investigate the dynamic and energetic properties of the dimer by molecular dynamics simulation. JAK2 activation requires the two domains to be dissociated and rearranged in a form such that the JH1 kinase domain can adopt an active conformation. The significance of the above mechanism is emphasized by the finding that the activating V617F mutation destabilizes JH1-JH2 association in the proposed asymmetric dimer. Thus abrogation of the domain-domain interaction seems to be a possible first step for the structural rearrangement of the two domains, resulting in constitutive activation of JAK2 by the V617F mutation.
Authors:
Shunzhou Wan; Peter Vivian Coveney
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-4
Journal Detail:
Title:  Journal of chemical information and modeling     Volume:  -     ISSN:  1549-960X     ISO Abbreviation:  J Chem Inf Model     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101230060     Medline TA:  J Chem Inf Model     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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