The G protein-coupled receptor (GPCR) melanocortin receptor 4 (MC4R) is an essential regulator of body weight homeostasis. MC4R is unusual among GPCRs in that its activity is regulated by 2 opposing p Show more
The G protein-coupled receptor (GPCR) melanocortin receptor 4 (MC4R) is an essential regulator of body weight homeostasis. MC4R is unusual among GPCRs in that its activity is regulated by 2 opposing physiological ligands, the agonist ⍺-MSH and the antagonist/inverse agonist AgRP. Paradoxically, while MC4R localizes and functions at the cilium of hypothalamic neurons, the ciliary levels of MC4R are very low under unrestricted feeding conditions. Here, we find that the constitutive activity of MC4R is responsible for the continuous depletion of MC4R from cilia and that inhibition of MC4R's activity via AgRP leads to a robust accumulation of MC4R in cilia. Ciliary targeting of MC4R is mediated by its partner MRAP2 and the constitutive exit of MC4R from cilia relies on the sensor of activation β-arrestin, on ubiquitination, and on the BBSome ciliary trafficking complex. Thus, while MC4R exits cilia via conventional mechanisms, it only accumulates in cilia when its activity is suppressed by AgRP. Show less
Interleukin-27 (IL-27) uniquely assembles p28 and EBI3 subunits to a heterodimeric cytokine that signals via IL-27Rα and gp130. To provide the structural framework for receptor activation by IL-27 and Show more
Interleukin-27 (IL-27) uniquely assembles p28 and EBI3 subunits to a heterodimeric cytokine that signals via IL-27Rα and gp130. To provide the structural framework for receptor activation by IL-27 and its emerging therapeutic targeting, we report here crystal structures of mouse IL-27 in complex with IL-27Rα and of human IL-27 in complex with SRF388, a monoclonal antibody undergoing clinical trials with oncology indications. One face of the helical p28 subunit interacts with EBI3, while the opposite face nestles into the interdomain elbow of IL-27Rα to juxtapose IL-27Rα to EBI3. This orients IL-27Rα for paired signaling with gp130, which only uses its immunoglobulin domain to bind to IL-27. Such a signaling complex is distinct from those mediated by IL-12 and IL-23. The SRF388 binding epitope on IL-27 overlaps with the IL-27Rα interaction site explaining its potent antagonistic properties. Collectively, our findings will facilitate the mechanistic interrogation, engineering, and therapeutic targeting of IL-27. Show less