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Publication Abstract from PubMed

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 to assess the functional significance of apparent differences in the receptor interaction sites (IL-6Ralpha and gp130) suggested by the fairly low degree of sequence similarity with human IL-6. Structure-based sequence alignment of mouse IL-6 and human IL-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-6Ralpha/gp130 ternary complex. This is further supported by a series of direct binding experiments, which clearly demonstrate a high affinity IL-6/IL-6Ralpha-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-6Ralpha/gp130 signaling complex and strategies for therapeutic targeting. We propose that the signaling complex originally involved specific interactions between IL-6 and IL-6Ralpha (site I) and between the D1 domain of gp130 and IL-6/IL-6Ralpha (site III), with the later inclusion of interactions between the D2 and D3 domains of gp130 and IL-6/IL-6Ralpha (site II) through serendipity. It seems likely that IL-6 signaling benefited from the evolution of a multipurpose, nonspecific protein interaction surface on gp130, now known as the cytokine binding homology region (site II contact surface), which fortuitously contributes to stabilization of the IL-6/IL-6Ralpha/gp130 signaling complex.

Conservation of functional sites on interleukin-6 and implications for evolution of signaling complex assembly and therapeutic intervention.,Veverka V, Baker T, Redpath NT, Carrington B, Muskett FW, Taylor RJ, Lawson AD, Henry AJ, Carr MD J Biol Chem. 2012 Nov 16;287(47):40043-50. doi: 10.1074/jbc.M112.405597. Epub, 2012 Oct 1. PMID:23027872^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.