Upon binding of one or more cytokine molecules to the extracellular portions of the membrane receptors, dimerization or oligomerization of one or more receptor components leads to the active cytokine receptor complex. Complex formation involves conformational changes in the intracellular parts of the receptor molecules, which initiate an intracellular signal cascade.
The composition of cytokine receptor complexes varies considerably . The simplest case is realized for growth hormone (GH) a member of the hematopoietin family (see Figure 3.1A). One GH molecule binds to two identical receptor (GHR) molecules . Interestingly, two complete different interaction sites (site I and site II) of GH interact with nearly the same residues in the two GHR molecules. Binding of the two receptor molecules happens sequentially, site I of the GH molecules first contacts one receptor molecule, followed by the contact of site II of GH and a second GHR .
In contrast to GH, many cytokines bind to heterodimeric receptor complexes. This is the case for IL-4 (Figure 3.1B) . This cytokine first binds to a receptor protein called IL-4R then to the common gamma chain (y C), a protein that is also used as a receptor molecule by many other cytokines (see below). Also cytokines of the IL-1 family bind to heterodimeric receptor complexes .
An even more complicated stochiometry is realized in the active receptor complexes of IL-6 (Figure 3.1C), IL-11, and ciliary neurotrophic factor (CNTF; Figure 3.1D). These cytokines have three distinct binding epitops (site I, site II, site III). Site I contacts a specific a-receptor (IL-6R, IL-11R, CNTFR). This contact is necessary for the binding of the cytokine to the signal-transducing subunits gp130 and leukemia inhibitory factor R (LIFR). In the case of IL-6 and IL-11, the cytokine/ a-receptor complex further interacts with two gp130-proteins (via site II and site III). In the case of CNTF, site II forms the contact to one gp130 molecule, whereas site III
42 Cytokines and the CNS
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