This domain can be found in leukemia inhibitory factor receptor (LIFR). LIFR is a cell surface receptor that mediates the actions of LIF and other interleukin-6 type cytokines through the formation of signalling complexes with gp130. This is the N-terminal domain, referred to as domain 1, which contains conserved disulfide bonds between Cys-10 to Cys-20 and Cys-37 to Cys-45 [].
This is the D2 domain in cytokine-binding module 1 (CBM1) found in Leukemia inhibitory factor receptor (LIFR) and OSM receptors (OSMR). LIFR has an extracellular region with a modular structure containing two cytokine-binding modules (CBM) separated by an Ig-like domain and followed by three membrane-proximal fibronectin type-III (FNIII) domains. The D2 domain in CBM1 shows structural similarity to the corresponding CBM domains of both gp130 and IL-6Ralpha because it contains conserved structural features like the WSXWS motif [, ]. The WSXWS motif in cytokine receptors is a molecular switch involved in receptor activation [].
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, an hematopoietin-receptor domain, and 3 fibronectin type-III domains (2 in the leptin receptor). This subgroup was designated as "Gp130 family of receptors"[]and contains the following chains: Leptin receptor (LPTR), Granulocyte colony stimulating factor receptor (GCSFR), Interleukin-6/-11/LIF/OSM/CNTF common beta chain (Gp130), Leukemia inhibiting factor receptor (LIFR), Oncostatin-M receptor beta chain (OSMR), Interleukin-12 receptor beta-1 chain (IL12RB1), Interleukin-12 receptor beta-2 chain (IL12RB2). A schematic representation of the structure of these receptors is shown below: +-------+-------------------------+-----------------xxxxxxx-----------------+|Ig-like| C C C C Extracellular | FnIII (x3) XXXXXXX Cytoplasmic |+-------+-|-|--|--|---------------+-----------------xxxxxxx-----------------+| | | | Transmembrane+-+ +--+These receptor chains homodimerize (GCSFR, Gp130, LPTR) or heterodimerize (Gp130 with LIFR or OSMR, IL12RB1 with IL12RB2) upon binding of the cognate cytokine: G-CSF, LIF, OSM, LPT, or the cytokine/alpha chain complex: IL-6/IL6RA, IL-11/IL11RA, CNTF/CNTFRA, IL-12 (p35/p40) [, ].
