The SOCS box encodes a hierarchy of affinities for Cullin5: implications for ubiquitin ligase formation and cytokine signalling suppression.

摘要: Abstract The SOCS (suppressors of cytokine signalling) family proteins inhibits the cytokine-induced signalling cascade in part by promoting ubiquitination intermediates that are then targeted for proteasomal degradation. This activity relies upon an interaction between box domain, adapter complex elonginBC and a member Cullin family, scaffold protein E3 ubiquitin ligase. In this study, we dissected vitro using purified components. We found all eight bound Cullin5 but required prior recruitment elonginBC. Neither nor when isolation. Interestingly, affinity each SOCS–elonginBC varied 2 orders magnitude across family. Unexpectedly, most potent suppressors signalling, SOCS-1 SOCS-3, weakly to ligase scaffold, with affinities 100- 10-fold lower, respectively, than rest remaining six high ( K d ∼ 10 nM) due slower off-rate hence longer half-life complex. difference may reflect mode action as only SOCS-3 have been shown suppress both box-dependent box-independent mechanisms. is not case other proteins, our data imply existence two distinct subclasses Cullin5, possibly reflecting complete dependence suppression signalling.