Receptor Recognition Sites of Cytokines Are Organized as Exchangeable Modules

Abstract

Interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) are "4-helical bundle" cytokines at the IL-6 type family of neuropoietic and hematopoietic cytokines. IL-6 signalsby induction of a gp 130 homodimer (e.g. IL-6), whereas CNTF and leukemia inhibitory factor (ILF) signal via a heterodimer of gp 130 and LIF receptor (LIFR). Despite binding to the same receptor component (gp130) and a similar protein structure, IL-6 and CNTF share only 6% sequence identity. Using molecular modeling we defines a putative LIFR binding epitope on CNTF that consists of three distinct regions (C-terminal A-helix/Nterminal AB loop, BC loop, C-terminal CD-loop/N-terminal D-helix). A corresponding gp 130-binding site on IL-6 was exchanged with this epitope. The sesulting IL-6/CNTF chimera lost the capacity to signal via gp 130 on cells without LIFR, but acquired the ability to signal via the gp 130/LIFR heterodimer and STATklein3 on responsive cells. Besides identifying a specife LIFR binding epiotope on CNTF, our results suggest that receptor recognition sites of cytokines are orgenized an modules that are exchangeable even between cytokines with limited sequences homology.