Structure of a pseudokinase domain switch that controls oncogenic activation of Jak kinases

The V617F mutation in the Jak2 pseudokinase domain causes myeloproliferative neoplasms, and the equivalent mutation in Jak1 (V658F) is found in T-cell leukemias. Crystal structures of wild type and V658F mutant human Jak1 pseudokinase reveal a conformational switch that remodels a linker segment encoded by exon 12, which is also a site of mutations in Jak2. This switch is required for V617F-mediated Jak2 activation, and possibly for physiologic Jak activation. The receptors for diverse cytokines, including erythropoietin (EPO), growth hormone, interleukins and interferons, initiate intracellular signaling via one or more members of the Jak family of non-receptor tyrosine kinases1,2. Jak kinases contain a FERM domain, an SH2-like domain, and a pseudokinase domain (also referred to as the Jak homology 2, or JH2 domain) adjacent to their C-terminal tyrosine kinase domain (Fig. 1a). The pseudokinase domain has a protein kinase fold, but key catalytic residues are not conserved and the domain is thought to inhibit the adjacent tyrosine kinase domain, perhaps via an intramolecular interaction3. Somatic gain-of-function mutations in Jaks underlie a number of hematologic malignancies4, and the pseudokinase domain is the most frequent site of thes