Feline Interleukin-31 Shares Overlapping Epitopes with the Oncostatin M Receptor and IL-31RA
journal contributionposted on 04.06.2020, 16:36 by Angelica V. Medina-Cucurella, Gary F. Bammert, William Dunkle, Christopher Javens, Yaqi Zhu, Veronica T. Mutchler, Janet T. Teel, Caitlin A. Stein, Steve A. Dunham, Timothy A. Whitehead
Interleukin-31 (IL-31) is a major protein involved in severe inflammatory skin disorders. Its signaling pathway is mediated through two type I cytokine receptors, IL-31RA (also known as the gp130-like receptor) and the oncostatin M receptor (OSMR). Understanding molecular details in these interactions would be helpful for developing antagonist anti-IL-31 monoclonal antibodies (mAbs) as potential therapies. Previous studies suggest that human IL-31 binds to IL-31RA and then recruits OSMR to form a ternary complex. In this model, OSMR cannot interact with IL-31 in the absence of IL-31RA. In this work, we show that feline IL-31 (fIL-31) binds independently with feline OSMR using surface plasmon resonance, an enzyme-linked immunosorbent assay, and yeast surface display. Moreover, competition experiments suggest that OSMR shares a partially overlapping epitope with IL-31RA. We then used deep mutational scanning to map the binding sites of both receptors on fIL-31. In agreement with previous studies of the human homologue, the binding site for IL31-RA contains fIL-31 positions E20 and K82, while the binding site for OSMR comprises the “PADNFERK” motif (P103–K110) and position G38. However, our results also revealed a new overlapping site, composed of positions R69, R72, P73, D76, D81, and E97, between both receptors that we called the “shared site”. The conformational epitope of an anti-feline IL-31 mAb that inhibits both OSMR and IL-31RA also mapped to this shared site. Combined, our results show that fIL-31 binds IL-31RA and OSMR independently through a partially shared epitope. These results suggest reexamination of the putative canonical mechanisms for IL-31 signaling in higher animals.
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anti-feline IL -31 mAbposition G 38.oncostatin M receptorfIL -31 positions E 20IL -31RAIL -31antagonist anti-IL -31enzyme-linked immunosorbent assaybinding site31-RAIL -31RA Interleukin -31PADNFERKyeast surface displaysurface plasmon resonancegp 130-like receptorFeline Interleukin -31 Shares Overlapping EpitopesOSMROncostatin M Receptor