Cytokine Receptor Subunit structure

The subunit structure of the cytokine receptors is very variable. Three representative cytokine receptor classes will be presented in the following, illustrating the interrelation between receptor subunit structure, ligand binding, and tyrosine kinase activation. 

FIGURE 27-3 Neurotrophic cytokines and their receptors. Neurotrophic cytokines are related to IL6 and bind to cell surface receptor complexes that share a common structural organization. The four ligands interchangeably employ two distinct receptor subunits, leukemia inhibitory factor receptor 3 (LIF-Rpt) andgpl30, and some employ a ligand-specific a subunit. CNTF-R, ciliary neurotrophic factor CT-fR.cardiotrophin 1 receptor IL6-R, interleukin-6 receptor. 

The subunit structure of the cytokine receptors is very variable. Amongst the cytokine receptors, there are receptors composed of one polypeptide and receptors made up of two or three different polypeptide chains (Fig. 11.3), which therefore have a hetero-oligomeric structure. The receptors have one transmembrane element per polypeptide chain. The NH2 terminus is located in the extracellular region whilst the CO OH terminus is intracellular. 

Fig. 11.3. Subunit structures of cytokine receptors. EpoR and G-CSFR have a homo-oligomeric structure. The other receptors shown are composed of different subunits, some of which occur in several receptors. The gpl30 subunit is common to IL-6R and LIF-R the Yc subunit is found in IL-2R and IL-4R. The subunits, at which ligand binding occurs, are indicated by arrows. LIF-R leukemia inhibitory factor receptor.

The group II receptor complexes of interferon- and IFN-o/P receptors will be presented as examples of cytokine-receptor complexes. They are expressed in nearly all cells. A three-dimensional structure of an interferon-y complex has been solved, it has two subunits, IFNyRl, (IFNGRl), and IFNyR2, (IFNGR2) (Fig. 6.8). 

One common feature of the cytokine receptor family, including the IL-6 family, is that its members contain immunoglobulin (Ig)-like domains, of which the structures are similar to that of Ig, in the extracellular site of each subunit (Bazan 1991). Near the C-terminal end of the second domain ( C-terminal domain), there is a cytokine receptor family consensus sequence, W(Trp)-S(Ser)-X(a variable residue)-W-S. 

Human GM-CSF receptor is composed of at least 2 subunits the 3-subunit is identical with a subunit of the receptors for interleukin-3 and interleukin-5. Both subunits have domains that are structurally related to a fibronectin type III domain, a structure that is conserved in all members of the cytokine receptor superfamily. Genomic DNA clones containing the entire coding sequence of the a-subunit have been isolated and characterized [Y.Nakagawa etal. J. Biol. Chem. 269 (1994) 10905-10912). 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

The presence of at least two chains is the common characteristic of many of these receptors. The cytokines having two chain structures exhibit dual affinity although there are some exceptions. The examples of receptors with two chain structures include sharing of y-y subunit of IL-2with IL-4, IL-7, IL-9, IL-15 and IL-21, common (3 chains of IL-3, IL-5 and GM-CSF and common a chain for IL-4 and IL-13. gpl30, which is a second chain required for IL-6-a activity, is also a trigger for several other cytokines. The binding of the cytokine to the double chain renders a dual affinity as is the case for IL-2, IL-3, IL-5, IL-7 and GM-CSF. 

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