Understanding complex formation of gp130 cytokines for the design of selective therapeutics

Cytokines activate their target cells via binding to specific receptors on the cell surface. The receptor glycoprotein 130 (gp130) is ubiquitously expressed throughout the human body and used by nine members of the interleukin-6 (IL-6) family of cytokines to facilitate the initiation of intracellular signalling cascades. Although these cytokines share the same protein fold, gp130 requires substantial promiscuity in order to bind such diverse proteins. In this review, we summarize what is currently known about the structural features of gp130 that allow this flexibility towards its binding partners. We compare this to the other non-signalling α-receptors and signal-transducing β-receptors of the family and discuss how IL-6 family cytokines form signalling complexes at the cell surface that lead to the activation of intracellular signalling cascades. We further show how mutations found in human patients influence gp130 signalling, and describe how such knowledge can be used to create tailor-made designer proteins that can be used as next-generation therapeutics for the treatment of inflammatory diseases.