Cytokine Signalling Forum

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Structural basis for the recognition of interferon-α receptor by tyrosine kinase 2

Wallweber HJA, Tam C, Franke Y et al. - Nat Struct Mol Biol. 2014 May;21(5):443-8. doi: 10.1038/nsmb.2807. Epub 2014 Apr 6

Janus kinases, JAKs, are essential in the mediation of cytokine and interferon signalling whilst also being crucial to body processes such as immune function, hematopoeises, metabolism and cellular growth. However, it is not known is how the four members of the JAK family interact with and are activated by over 30 cytokine receptors with near perfect affinity and specificity.
Currently, there are no crystal structures available for any JAK bound to a cytokine receptor. This study sought address this by determining the structure of the FERM and SH-2 domains from human TYK2 when bound to a peptide from interferon-a receptor chain 1 (IFNAR1). By elucidating this structure, this should remove the currently limited interpretation of receptor-interaction sequences.
The structural work done in this study indicates a multipoint JAK-interaction blueprint for receptors using the conserved SH2-box2 interaction, typified by TYK2 and IFNAR1, and interactions with box1 and other motifs. These interactions are used to secure a tight interface between JAK and receptor. It is this arrangement which appears to allow high fidelity and specificity in the coupling of the broad family of cytokine receptors with their respective downstream signalling amplifiers.