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




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BMC Structural Biology

, 9:58

First Online: 10 September 2009Received: 21 May 2009Accepted: 10 September 2009

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.

Electronic supplementary materialThe online version of this article doi:10.1186-1472-6807-9-58 contains supplementary material, which is available to authorized users.

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Author: Tai-Sung Lee - Wanlong Ma - Xi Zhang - Hagop Kantarjian - Maher Albitar

Source: https://link.springer.com/







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