Structural effects of clinically observed mutations in JAK2 exons 13-15: comparison with V617F and exon 12 mutations

Simulation 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.The 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.Protein kinases play critical key roles in cellular signal transduction and can be activated by either phosphorylation or interaction with other proteins or ligands [1-4]. However, 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. In many protein kinases, activity is regulated by the coupling between the C-helix and regulatory domains [5-7]. In others, the catalytic domains act as their own regulatory regions [8,9]. Recently, the MAP2K MEK6 was demonstrated to be auto-regulated via the formation of a symmetrical dimer [10].Janus kinase 2 (JAK2) is a protein tyrosine kinase that transduces cellular signals through the JAK-STAT pathways [11,12]. Deregulation of JAK2 is thought to be associated with hematopoietic disorders and oncogenesis [13-17], especially in patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs) [18]. Howe