Ciliary neurotrophic factor (CNTF) is a member of the gp130 family of cytokines. CNTF is a survival factor for various neuronal cell types and seems to prevent the degeneration of motor axons after axotomy suggesting it may be a potential therapeutic for treating neurodegeneration and nerve injury. CNTF acts on oligodendrocytes by favoring their final maturation, and this effect is mediated through the 130kDa glycoprotein receptor common to the CNTF family and transduced through the Janus kinase pathway. The functional receptor complex of CNTF is composed of the CNTF receptor alpha (CNTFR), gp130 and the leukemia inhibitory factor receptor (LIFR). The structure of CNTF is a four helical bundle []. CNTF acts as a homodimer. Three regions on CNTF have been identified as binding sites for its receptors. The ligand-receptor interactions are mediated through the cytokine binding domains (CBDs) and/or the immunoglobulin-like domains of the receptors. However, in the case of CNTF, the precise nature of the protein-protein contacts in the signalling complex has not yet been resolved, but there is evidence that the membrane distal CBD (CBD1) of LIFR associates in vitro with soluble CNTFR in the absence of CNTF [, ].
A number of receptors for lymphokines, hematopoietic growth factors and growth hormone-related molecules have been found to share a common binding domain. These receptors are designated as hematopoietin receptors []and the corresponding ligands as hematopoietins. Further, hematopoietins have been subdivided into two major structural groups: Large/long and small/short hematopoietins.One subset of individual receptor chains that are part of receptor complexes for large hematopoietins contain common structural elements in their extracellular parts: an immunoglobulin-like domain at the N-terminal end of the hematopoietin receptor domain (except for the EBCV-induced interleukin-12beta chain) and a short (or no) cytoplasmic domain. They define a structural subgroup containing the following chains: Interleukin-6 receptor alpha chain (IL6RA). Interleukin-11 receptor alpha chain (IL11RA), Ciliary neurotrophic factor receptor alpha chain (CNTFRA), Interleukin-12 beta chain p40 (IL12BC), Interleukin-12 beta chain induced by Epstein-Barr virus (strain GD1) (HHV-4) (Human herpesvirus 4).Members of this subgroup bind to their cognate cytokines with low affinity and possess transmembrane and short cytoplasmic domains (IL6RA and IL11RA), or are GPi-linked membrane proteins (CNTFRA). Truncated soluble forms of IL-6 and CNTF receptors alpha chains are physiologically active []. IL-12 is an heterodimeric cytokine made of an alpha chain (p35) and a beta chain (p40). p40 (IL12BC) can be regarded as an alpha chain receptor devoid of cytoplasmic domain []. Members of this family have the ability to bind corresponding cytokines with no signalling function.
