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

Lupardus PJ, Ultsch M, Wallweber H et al. - Proc Natl Acad Sci U S A. 2014 May 19. pii: 201401180. [Epub ahead of print]

The JAK family of kinases (JAK1, JAK2, JAK3 and TYK2) are receptor-associated tyrosine kinases that act downstream of many cytokines and interferons. Recent studies have provided structural information about the kinase and pseudokinase domains of JAKs however the molecular mechanism by which JAK activity is regulated by the pseudokinase domain is poorly understood.
This study builds on a recent finding that the N terminus of the JAK1 pseudokinase group may act as a switch for kinase activation by presenting a 2.8Å crystal structure of both the kinase and pseudokinase domains of TYK2.
The structure shows the TYK2 pseudokinase interacts with the kinase via a composite interface formed by the pseudokinase N-lobe and the N-lobe “exon-12” segment. The mapping of JAK mutations onto the structure as well as kinase activity measurements of interface mutants, indicates this is an autoinhibitory interface that, if disrupted, relieves kinase inhibition and can initiate JAK-mediated malignancies.

Keywords: JAK, Preclinical, MOA

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Upload date: June 2014

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