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Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

2014; National Academy of Sciences; Volume: 111; Issue: 22 Linguagem: Inglês

10.1073/pnas.1401180111

1091-6490

Patrick J. Lupardus, Mark Ultsch, Heidi J.A. Wallweber, Pawan Bir Kohli, Adam R. Johnson, Charles Eigenbrot,

Pharmacological Effects of Natural Compounds

Significance Cytokine signaling is essential for cell growth, hematopoiesis, and immune system function. Cytokine-mediated receptor dimerization induces intracellular activation of receptor-bound Janus kinases (JAKs), which then induce downstream transcriptional responses. We have determined a two-domain crystal structure containing the pseudokinase and kinase domains from the JAK family member TYK2, which identifies an inhibitory interaction interface between the two domains. Cancer-associated mutations found in other JAK family members map to this inhibitory interaction site, whereas analogous mutations in TYK2 cause in vitro activation of the kinase. This study identifies a mechanism for pseudokinase-mediated autoinhibition of the TYK2 kinase domain and suggests a means by which cancer-associated JAK mutations induce aberrant kinase activity.