Abstract：
:Janus kinase 2 (JAK2) is a protein tyrosine kinase implicated in signaling 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.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Wan S,Coveney PVdoi
10.1021/ci300308gsubject
Has Abstractpub_date
2012-11-26 00:00:00pages
2992-3000issue
11eissn
1549-9596issn
1549-960Xjournal_volume
52pub_type
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