Evaluation of the Structural Impact of the Missense Mutation JAK2 V617F in Janus Kinase 2 by Docking Study

Abstract

Myeloproliferative neoplasm is a group of blood cancers, including three main diseases: essential thrombocythemia, primary myelofibrosis, and polycythemia vera. Several molecular signaling pathways such as JAK/STAT, PI3K or SHP have been demonstrated that play a crucial role in controlling the signaling-mediated immune response related to Myeloproliferative neoplasms. The mutation JAK2 V617F substitutes phenylalanine for valine at position 617 in the JH2 domain of exon 14, leading to constitutive activation of the JAK-STAT and other pathways resulting in uncontrolled cell growth. This mutation has been found in a large proportion of myeloproliferative neoplasm patients. In this study, we performed a docking simulation test by Yasara, Pyrx, and Pymol to evaluate the effect of this variant on the model structure of the JH2 domain compared to wild-type allele, thus verifying the impact of mutation V617F on the function of Janus Kinase. The result showed that there was a significant effect that this mutation can cause on the interaction between the JH2 model and ATP. In detail, after redocking simulation, the wild type structure showed 16 hydrogen bonds binding between ATP and amino acids including T555, T557, K581, Q626, E627, N673, K677, P700, and R715 with the binding energy of -10 (kcal/mol), while the mutant model expressed 15 hydrogen bonds linked with the amino acids of T555, T557, K581, Q626, E627, N673, K677, and N678, with the binding energy of -9.6 (kcal/mol). This result may provide a better understanding of the critical role of Janus kinase in the pathogenesis of myeloproliferative disorders.