Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition.
Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain via an unknown mechanism. Here, we report the 2.8-Å structure of the two-domain pseudokinase-kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudokinase and kinase interact near the kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and "exon 12" JAK2 mutations, results in increased kinase activity in vitro. These data indicate that JAK pseudokinases are autoinhibitory domains that hold the kinase domain inactive until receptor dimerization stimulates transition to an active state.
Departments of Structural Biology and lupardus.patrick@gene.com eigenbrot.c@gene.com.
Patrick J
PJ
Lupardus
Departments of Structural Biology and.
Mark
M
Ultsch
Departments of Structural Biology and.
Heidi
H
Wallweber
Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA 94080.
Pawan
P
Bir Kohli
Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA 94080.
Adam R
AR
Johnson
Departments of Structural Biology and lupardus.patrick@gene.com eigenbrot.c@gene.com.
Charles
C
Eigenbrot
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D019281:Dimerization; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D007313:Insecta / Q000166:cytology; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D053634:TYK2 Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D053634:TYK2 Kinase; C070139:TYK2 protein, human
JAK1; JAK3