Identification of an Acquired Mutation in Jak2 Provides Molecular Insights into the Pathogenesis of Myeloproliferative Disorders

A schematic structure of Jak2-JH1-2 domains and predicted effect of the V617F mutation. The putative spatial orientation of JH1 and JH2 domains on the structure of growth factor receptor is shown. The JH1-JH2 interaction site, including the site of V⁶¹⁷, is circled. The activation loop of JH1 has two possible conformations (active-red, inactive-purple); the ATP binding site is shown in yellow. It is thought that the JH2 can negatively regulate the JH1 or kinase domain. It is proposed that the V617F mutation destabilizes the JH1-JH2 interaction and thereby promotes activation of kinase activity. From Kaushansky, K. On the molecular origins of the chronic myeloproliferative disorders: It all makes sense. Blood 105, 4187–4190 (2005). Copyright American Society of Hematology, used with permission (39).