title: Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases.
abstract: 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.
authors.affiliation: 1] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Angela V
authors.initials: AV
authors.lastname: Toms
authors.forename: Anagha
authors.initials: A
authors.lastname: Deshpande
authors.forename: Randall
authors.initials: R
authors.lastname: McNally
authors.forename: Youngjee
authors.initials: Y
authors.lastname: Jeong
authors.forename: Julia M
authors.initials: JM
authors.lastname: Rogers
authors.forename: Chae Un
authors.initials: CU
authors.lastname: Kim
authors.forename: Sol M
authors.initials: SM
authors.lastname: Gruner
authors.forename: Scott B
authors.initials: SB
authors.lastname: Ficarro
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.forename: Martin
authors.initials: M
authors.lastname: Sattler
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
mesh_terms: D004789:Enzyme Activation; D006801:Humans; D053612:Janus Kinases / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D009857:Oncogenes; D011487:Protein Conformation
chemical_list: D053612:Janus Kinases