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Title: Conservation of functional sites on interleukin-6 and implications for evolution of signalling complex assembly and therapeutic intervention.
Authors: Veverka, V
Baker, T
Redpath, NT
Carrington, B
Muskett, FW
Taylor, RJ
Lawson, AD
Henry, AJ
Carr, MD
First Published: 1-Oct-2012
Citation: J BIOL CHEM, 2012
Abstract: A number of secreted cytokines, such as interleukin-6 (IL-6), are attractive targets for the treatment of inflammatory diseases. We have determined the solution structure of mouse IL-6 (mIL-6) to assess the functional significance of apparent differences in the receptor interaction sites (IL-6Rα and gp130) suggested by the fairly low degree of sequence similarity with human IL-6 (hIL-6). Structure-based sequence alignment of mIL-6 and hIL-6 revealed surprising differences in the conservation of the two distinct gp130 binding sites (IIa and IIIa), which suggests a primacy for site III-mediated interactions in driving initial assembly of the IL-6/IL-6Rα/gp130 ternary complex. This is further supported by a series of direct binding experiments, which clearly demonstrate a high affinity IL-6/IL-6Rα-gp130 interaction via site III but only weak binding via site II. Collectively, our findings suggest a pathway for the evolution of the hexameric, IL-6/IL-6Rα/gp130 signalling complex and strategies for therapeutic targeting. We propose that the signalling complex originally involved specific interactions between IL-6 and IL-6Rα (site I), and between the D1 domain of gp130 and IL-6/IL-6Rα (site III), with the later inclusion of interactions between the D2 and D3 domains of gp130 and IL-6/IL-6Rα (site II) through serendipity. It seems likely that IL-6 signalling benefited from the evolution of a multi-purpose, non-specific protein interaction surface on gp130, now known as the cytokine-binding homology region (site II contact surface), which fortuitously contributes to stabilisation of the IL-6/IL-6Rα/gp130 signalling complex.
DOI Link: 10.1074/jbc.M112.405597
eISSN: 1083-351X
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Biochemistry

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