The structure of the unliganded extracellular domain of the interleukin-6 signal transducer gp130 in solution

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• 作者：Inken Lorenzen^a ; ¹ ; Weifeng Shang^b ; ¹ ; Markus Perbandt^d ; ^e ; Maxim V. Petoukhov^b ; Dmitri I. Svergun^b ; Georg H. Waetzig^c ; Stefan Rose-John^a ; Rolf Hilgenfeld^d ; ^e ; Joachim Grö ; tzinger^a ; ^{jgroetzinger@biochem.uni-kiel.de"" rel=""nofollow}
• 关键词：Interleukin-6 ; gp130 ; Trans-signalling ; Structure ; Small-angle X-ray scattering ; Rigid-body modelling
• 刊名：European Journal of Cell Biology
• 出版年：2011
• 出版时间：June-July 2011
• 年：2011
• 卷：90
• 期：6-7
• 页码：515-520
• 全文大小：1067 K

文摘

Interleukin-6 (IL-6) plays an important role in immune responses and signals via two different pathways. When IL-6 binds to its non-signalling membrane-bound receptor (IL-6R), a non-covalent dimer of the ubiquitous interleukin-6 signal transducer gp130 is recruited to initiate intracellular signalling cascades. This so-called classical signalling pathway is restricted to cells expressing the membrane-bound IL-6R, such as hepatocytes and certain leukocytes. In addition, an alternative trans-signalling pathway uses soluble forms of IL-6R (sIL-6R) in complex with IL-6 to activate cells expressing gp130, but not membrane-bound IL-6R. In both cases, a tetrameric or hexameric signalling complex consisting of two gp130 molecules and one or two molecules each of IL-6 and (s)IL-6R is formed. The structure of the hexameric complex of the ligand-binding domains of gp130 (D1–D3) with IL-6 and sIL-6R has been solved by X-ray crystallography as well as the full-length extracellular part of gp130 (D1–D6) as a monomer. Since gp130 exists as a preformed dimer on the cell surface, we used a sgp130Fc fusion protein – consisting of two extracellular gp130 regions (D1–D6) dimerised by an IgG1-Fc part – to study the structure of unliganded gp130 extracellular domains in solution by small-angle X-ray scattering (SAXS). The SAXS data indicated that sgp130Fc forms a rigid molecule in solution. The low resolution structural model reveals an elongated assembly with an Fc base and two gp130 arms, whereby the orientation of the ligand-binding domains D1–D3 with respect to the membrane-proximal domains D4–D6 differs from that in the crystallographic monomer. Functional implications of these findings are discussed.