Receptor recognition sites of cytokines are organized as exchangeable modules - Transfer of the leukemia inhibitory factor receptor-binding site fromciliary neurotrophic factor to interleukin-6

Interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) are "4-helical bundle" cytokines of the IL-6 type family of neuropoietic and hematopoietic cytokines, IL-6 signals by induction of a gp130 homodimer (eg. IL-6), wher eas CNTF and leukemia inhibitory factor (LIF) signal via a heterodimer of g p130 and LIF receptor (LIFR). Despite binding to the same receptor componen t (gp130) and a similar protein structure, IL-6 and CNTF share only 6% sequ ence identity. Using molecular modeling we defined a putative LIFR binding epitope on CNTF that consists of three distinct regions (C-terminal A-helix /N-terminal AB loop, BC loop, C-terminal CD-loop/N-terminal D-helix), A cor responding gp130-binding site on IL-6 was exchanged with this epitope, The resulting IL-6/CNTF chimera lost the capacity to signal via gp130 on cells without LIFR, but acquired the ability to signal via the gp130/LIFR heterod imer and STATE on responsive cells. Besides identifying a specific LIFR bin ding epitope on CNTF, our results suggest that receptor recognition sites o f cytokines are organized as modules that are exchangeable even between cyt okines with limited sequence homology.