Journal article

The molecular basis of JAK/STAT inhibition by SOCS1

Nicholas PD Liau, Artem Laktyushin, Isabelle S Lucet, James M Murphy, Shenggen Yao, Eden Whitlock, Kimberley Callaghan, Nicos A Nicola, Nadia J Kershaw, Jeffrey J Babon

NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2018

Abstract

The SOCS family of proteins are negative-feedback inhibitors of signalling induced by cytokines that act via the JAK/STAT pathway. SOCS proteins can act as ubiquitin ligases by recruiting Cullin5 to ubiquitinate signalling components; however, SOCS1, the most potent member of the family, can also inhibit JAK directly. Here we determine the structural basis of both these modes of inhibition. Due to alterations within the SOCS box domain, SOCS1 has a compromised ability to recruit Cullin5; however, it is a direct, potent and selective inhibitor of JAK catalytic activity. The kinase inhibitory region of SOCS1 targets the substrate binding groove of JAK with high specificity and thereby blocks a..

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Grants

Awarded by Cancer Council Victoria


Awarded by National Health and Medical Research Council (NHMRC) Australia


Awarded by NHMRC IRIISS


Funding Acknowledgements

This work was supported by the Cancer Council Victoria (Grant-in-aid 1065180) and the National Health and Medical Research Council (NHMRC) Australia (Project grant #1122999, Program grant #1113577), an NHMRC IRIISS grant 9000220, and a Victorian State Government Operational Infrastructure Scheme grant. J.J.B., J.M.M. and N.A.N. are supported by NHMRC fellowships and NPDL by an Australian Postgraduate Award. We thank the scientists at the MX beamline at the Australian Synchrotron. Crystallization trials were performed at CSIRO collaborative crystallization centre (C3)