Abstract
BackgroundThe functional relevance of many of the recently detected JAK2 mutations, except V617F and exon 12 mutants, in patients with chronic myeloproliferative neoplasia (MPN) has been significantly overlooked. To explore atomic-level explanations of the possible mutational effects from those overlooked mutants, we performed a set of molecular dynamics simulations on clinically observed mutants, including newly discovered mutations (K539L, R564L, L579F, H587N, S591L, H606Q, V617I, V617F, C618R, L624P, whole exon 14-deletion) and control mutants (V617C, V617Y, K603Q/N667K).ResultsSimulation results are consistent with all currently available clinical/experimental evidence. The simulation-derived putative interface, not possibly obtained from static models, between the kinase (JH1) and pseudokinase (JH2) domains of JAK2 provides a platform able to explain the mutational effect for all mutants, including presumably benign control mutants, at the atomic level.ConclusionThe results and analysis provide structural bases for mutational mechanisms of JAK2, may advance the understanding of JAK2 auto-regulation, and have the potential to lead to therapeutic approaches. Together with recent mutation profiling results demonstrating the breadth of clinically observed JAK2 mutations, our findings suggest that molecular testing/diagnostics of JAK2 should extend beyond V617F and exon 12 mutations, and perhaps should encompass most of the pseudo-kinase domain-coding region.
Highlights
The functional relevance of many of the recently detected Janus kinase 2 (JAK2) mutations, except V617F and exon 12 mutants, in patients with chronic myeloproliferative neoplasia (MPN) has been significantly overlooked
Three key groups of interactions are shown: I-1 is the helix-helix interactions between the JH1 C-helix and the JH2 C-helix; I-2 is the interactions between the JH1 activation loop (A-loop) and the JH2 C-helix; and I-3 is the interactions between the activation loop of JH1 and a region of contact in JH2, including V617
Ma et al [34] recently reported detection of several mutations in exons 12 to 15, based on analysis of approximately 20,000 clinical blood samples. Their findings suggested that molecular testing of JAK2 mutations should not be restricted to the V617F and exon 12 mutations, but perhaps should extend to most of the JH2 pseudo-kinase domain
Summary
The functional relevance of many of the recently detected JAK2 mutations, except V617F and exon 12 mutants, in patients with chronic myeloproliferative neoplasia (MPN) has been significantly overlooked. Protein kinases play critical key roles in cellular signal transduction and can be activated by either phosphorylation or interaction with other proteins or ligands [1,2,3,4]. Surprisingly little is known about protein-protein interactions involved in kinase activation processes. Scaffolds have been shown as allosteric regulators of kinases; symmetrical dimers of kinases could be involved in auto-phosphorylation regulation; and many protein kinases may be regulated via N-lobe interactions. BMC Structural Biology 2009, 9:58 http://www.biomedcentral.com/1472-6807/9/58 protein kinases, activity is regulated by the coupling between the C-helix and regulatory domains [5,6,7]. The MAP2K MEK6 was demonstrated to be auto-regulated via the formation of a symmetrical dimer [10]
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