Inhibition of JAK signalling by SOCS1 (#288)
Hypothesis
The Janus Kinase family of proteins (JAKs) are constitutively associated with the intracellular portion of cytokine receptors. Upon cytokine stimulation of the receptor, JAKs provide the kinase activity necessary for the phosphorylation of substrate molecules, resulting in a subsequent biological response. The Suppressors of Cytokine Signalling (SOCS) proteins inhibit JAK activity, regulating cytokine signalling. SOCS1 and SOCS3 have a distinct method of inhibiting JAK1, JAK2 and TYK2 by competing with protein substrates, directly inhibiting JAK catalytic activity.
We have solved the structure of SOCS3 in complex with JAK2 and a fragment of the gp130 receptor. This structure shows that SOCS3 binds JAK and receptor simultaneously. Importantly, SOCS3 is able to obtain specificity for the downregulation of certain cytokine pathways by binding preferentially to some receptors.
In light of this information, we now aim to elucidate the mechanism through which the similar SOCS1 inhibits JAK catalytic activity.
Aims and methods
We have recently been able to recombinantly produce SOCS1, allowing structural and biophysical studies to be undertaken for the first time.
Our preliminary data indicate that SOCS1 is a more potent inhibitor of JAK catalytic activity than SOCS3. We are currently investigating the structural features of SOCS1 which contribute to such inhibitory activity. We are also investigating the features allowing SOCS1 to specifically inhibit different cytokine pathways to those regulated by SOCS3.
Specifically, we aim to obtain the structure of SOCS1 bound to a JAK family member to understand its mode of inhibition. Further, studies of engineered SOCS1 and JAK mutants can now reveal the direct contributions of particular regions of each protein to binding and inhibition kinetics, as well as those regions which provide specificity of inhibition of certain cytokine pathways.
- Kershaw, N.J., et al., SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nature structural & molecular biology, 2013. 20(4): p. 469-76.
- Babon, J.J., et al., Suppression of cytokine signaling by SOCS3: characterization of the mode of inhibition and the basis of its specificity. Immunity, 2012. 36(2): p. 239-50.