2L3Y

Solution structure of mouse IL-6

2L3Y の概要

• エントリーDOI: 10.2210/pdb2l3y/pdb
• 分子名称: Interleukin-6 (1 entity in total)
• 機能のキーワード: cytokine, interleukin, signaling, gp-130, transcription
• 由来する生物種: Mus musculus (mouse)
• 細胞内の位置: Secreted: P08505
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 21922.92

構造登録者

Veverka, V.,Redpath, N.T.,Carrington, B.,Muskett, F.W.,Taylor, R.J.,Henry, A.J.,Carr, M.D. (登録日: 2010-09-25, 公開日: 2011-09-28, 最終更新日: 2024-10-30)

主引用文献

Veverka, V.,Baker, T.,Redpath, N.T.,Carrington, B.,Muskett, F.W.,Taylor, R.J.,Lawson, A.D.,Henry, A.J.,Carr, M.D.
Conservation of functional sites on interleukin-6 and implications for evolution of signaling complex assembly and therapeutic intervention.
J.Biol.Chem., 287:40043-40050, 2012

PubMed 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 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. 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-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 signaling complex and strategies for therapeutic targeting. We propose that the signaling 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 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-6Rα/gp130 signaling complex.

PubMed: 23027872
DOI: 10.1074/jbc.M112.405597

実験手法

SOLUTION NMR