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 any subsequent phosphorylation. SOCS1 is a potent inhibitor of the interferon gamma (IFNγ) pathway, however, it does not bind the IFNγ receptor, making its mode-of-action distinct from SOCS3. These findings reveal the mechanism used by SOCS1 to inhibit signalling by inflammatory cytokines.

Details

Title
The molecular basis of JAK/STAT inhibition by SOCS1
Author
Liau, Nicholas P D 1 ; Laktyushin, Artem 1 ; Lucet, Isabelle S 1 ; Murphy, James M 1 ; Yao, Shenggen 2 ; Whitlock, Eden 1 ; Callaghan, Kimberley 1 ; Nicola, Nicos A 1 ; Kershaw, Nadia J 1 ; Babon, Jeffrey J 1   VIAFID ORCID Logo 

1  Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, VIC, Australia; The University of Melbourne, Royal Parade, Parkville, VIC, Australia 
2  The University of Melbourne, Royal Parade, Parkville, VIC, Australia 
Pages
1-14
Publication year
2018
Publication date
Apr 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-04013-1
ProQuest document ID
2027570523
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.