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Effects of JAK2 V556F Mutation on the JAK2's Activity, Structural Stability and the Transformation of Ba/F3 Cells

Effects of JAK2 V556F Mutation on the JAK2's Activity, Structural Stability and the Transformation of Ba/F3 Cells

Qing-Yun Wu, Meng-Meng Ma, Yu-Xue Tong, Yuan-Yuan Zhu, Yang Liu, Jiang Cao, Ping Zhou, Zhen-Yu Li, Ling-Yu Zeng, Xiao-Yun Wang, Feng Li, Kai-Lin Xu

Int J Biol Macromol. 2018 Oct 1;117:271-279.

PMID: 29842959

Abstract:

Although roles of somatic JAK2 mutations in clonally myeloproliferative neoplasms (MPNs) are well established, roles of germline JAK2 mutations in the pathogenesis of MPNs remain unclear. Recently, a novel activating, germline JAK2 F556V mutation was identified and involved in the pathogenesis of MPNs, but, its pathogenesis mechanism was still unknown. In this study, homology models of JAK2 demonstrated that F556 located between two threonine residues which interacted with ATP phosphate groups by hydrogen bonds, Thr555 with the γ-phosphate and Thr557 with the β-phosphate in the active site of JAK2's JH2 domain. Moreover, the hydrogen bond between Thr557 and Arg715 played vital roles in sustaining the structural conformation of JH2's active site and JH1-JH2 domains' interactions. When F556 was replaced by other amino acids except Trp, the hydrogen bond, JH2 domain's structural conformation and JH1-JH2 domains' interactions disrupted for changing the helix between β2 and β3 strands which finally caused JAK2 activation. Mechanistic and functional studies showed that JAK2 F556V mutation disrupted JAK2 JH2 domain's activity, caused JAK2-STAT5 pathway activation and promoted the proliferation of BaF3 cells. Thus, our results herein may provide clues to understand the pathogenesis mechanism of JAK2 F556V mutation in the MPNs.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42416390	Jak2 Jh1Jh2 Active human			Price

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