Journal article
SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition
NJ Kershaw, JM Murphy, NPD Liau, LN Varghese, A Laktyushin, EL Whitlock, IS Lucet, NA Nicola, JJ Babon
Nature Structural and Molecular Biology | Published : 2013
DOI: 10.1038/nsmb.2519
Abstract
The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus kinases (JAKs) that initiate signaling within the cell. We determined the crystal structure of a ternary complex between mouse SOCS3, JAK2 (kinase domain) and a fragment of the interleukin-6 receptor β-chain. The structure shows that SOCS3 binds JAK2 and receptor simultaneously, using two opposing surfaces. While the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by receptor, JAK2 binds in a phosphoindependent manner to a noncanonical surface. The kinase-inhibitory region ..
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Awarded by National Health and Medical Research Council
Funding Acknowledgements
We thank P. Colman, P. Czabotar and M. Lawrence for advice and I. Segel for helpful discussions. This work was supported in part by the National Health and Medical Research Council of Australia (NHMRC), program grants 461219 and 1016647 (N.A.N.) and project grant 1011804 (J.J.B.), the US National Institutes of Health CA22556 (N.A.N.), the Victorian State Government Operational Infrastructure Support grant and the NHMRC Independent Research Institutes Infrastructure Support Scheme (361646). N.A.N. acknowledges fellowship support from the NHMRC, J.M.M. and J.J.B. from the Australian Research Council and L.N.V. from the Leukaemia Foundation of Australia and the Australian Stem Cell Centre. We thank the scientists at the MX and SAXS/WAXS beamlines at the Australian Synchrotron. Crystallization trials were performed at CSIRO collaborative crystallization centre (C3).