Lee Tai-Sung, Ma Wanlong, Zhang Xi, Kantarjian Hagop, Albitar Maher
Biomedical Informatics and Computational Biology, and Department of Chemistry, University of Minnesota, 207 Pleasant Street, S.E., Minneapolis, MN 55455, USA.
BMC Struct Biol. 2009 Sep 10;9:58. doi: 10.1186/1472-6807-9-58.
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. 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).
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.
除V617F和外显子12突变体外，许多最近在慢性骨髓增殖性肿瘤（MPN）患者中检测到的JAK2突变的功能相关性被严重忽视。为了从原子层面解释这些被忽视突变体可能的突变效应，我们对临床观察到的突变体进行了一系列分子动力学模拟，包括新发现的突变（K539L、R564L、L579F、H587N、S591L、H606Q、V617I、V617F、C618R、L624P、整个外显子14缺失）和对照突变体（V617C、V617Y、K603Q/N667K）。
模拟结果与所有现有的临床/实验证据一致。JAK2激酶（JH1）和假激酶（JH2）结构域之间的模拟推导的假定界面（这是静态模型无法得到的）提供了一个平台，能够在原子层面解释所有突变体的突变效应，包括推测为良性的对照突变体。
这些结果和分析为JAK2的突变机制提供了结构基础，可能会增进对JAK2自身调节的理解，并有可能带来治疗方法。结合最近的突变谱分析结果表明临床观察到的JAK2突变范围很广，我们的发现表明JAK2的分子检测/诊断应超越V617F和外显子12突变，或许应涵盖大部分假激酶结构域编码区域。
