Untersuchungen zur Zytokinbindung und Rezeptoraktivierung des Signaltransduktors gp130 durch seine Liganden IL-6 und IL-11
The glycoprotein 130 (gp130) is expressed as a transmembrane receptor on the cellsurface of many cells. It acts as the central signal transducing subunit of the family of IL-6-type cytokines thereby initiating several biological responses. The aim of this work was to characterize the properties of ligand binding and activation of gp130 in detail: - Two different binding epitopes are required for ligand binding of the gp130 homodimerizing cytokines. One contact is provided by a region in the cytokine-binding module (CBM) of the receptor. The respective amino acids are in analogous position to the important residues within the CBM of the growth hormone receptor binding the growth hormone. The latter receptor belongs to a family of short-chain cytokine receptors. - A second contact region between gp130 and the homodimerizing ligands is provided by the Ig-like domain of the receptor thereby forming an asymmetrical dimer in complex with IL-6/IL-6R and IL-11/IL-11R. - The three membrane-proximal domains of gp130 (D4, D5 and D6) are responsible for the activation of the receptor. The deletion of D4 and D6 of gp130 leads to a partial loss of the cytokine binding affinity due to a conformational change. The deletion of D5 of gp130 does not influence the binding properties. - D4, D5 and D6 are all indispensable for receptor activation by cytokines. Cytokine independent activation by agonistic antibodies leads to partial activation of the receptor lacking domain 4 or 6. In contrast domain 5 is absolutely essential for the activation by these stimuli. - The important role of D5 of gp130 is also shown by replacing this domain with the analogous domain of the GCSFR. This chimeric receptor leads to a constitutively active receptor variant, highlighting this domain as important for receptor activation. - The results point towards a functional dichotomy of gp130 into a ligand binding and a receptor activating region.
info:eu-repo/classification/ddc/610, Cytokine, Rezeptor, Bindestelle, Interleukin 6, Interleukin 11, Aktivierung <Chemie>, Medizin, Zytokine, Rezeptoren, Immunologie
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