The Suppressors of Cytokine Signalling (SOCS) are negative regulators of cytokine signalling, which function by downregulating Janus Kinase (JAK) activity. SOCS1 and SOCS3, which are close homologues, have a distinct method of inhibiting JAK1, JAK2 and TYK2 by directly inhibiting JAK catalytic activity through a SOCS domain known as the Kinase Inhibition Region (KIR).
We have solved the structure of SOCS1 bound to JAK1, demonstrating that SOCS1 inhibits JAK1 catalytic activity by blocking substrate access to the JAK active site with its KIR domain. Our lab had previously shown that SOCS3 inhibits JAK catalytic activity in a similar manner. It had also been shown that SOCS3 obtains specificity for particular cytokine pathways by specifically targeting a portion of the relevant cytokine receptor with its SH2 domain.
However it appears that, at least in some cases, SOCS1 has a different mechanism of obtaining specificity for cytokine pathways to that of SOCS3. Specifically, it appears that SOCS1 has a novel mechanism for specifically downregulating interferon gamma signalling. We are currently investigating the structural features of SOCS1 which contribute to such specificity. Current biochemical data suggests that, rather than cytokine receptors being the target of the SOCS1 SH2 domain, the activation loop of JAK interacts with the SOCS1 SH2 domain.
We aim to obtain further functional data to elucidate the specific features of the JAK-IFNGR complex which result in downregulation by SOCS1. We aim to obtain further structures of SOCS1 bound to a JAK and/or a JAK-receptor complex which reveal the structural basis for this specificity.