Journal Article

FZJ-2014-05647

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Functional implications of large backbone amplitude motions of the glycoprotein 130-binding epitope of interleukin-6

Bobby, R. ; Robustelli, P. ; Kralicek, A. V. ; Mobli, M. ; King, G. F. ; Grötzinger, J. ; Dingley, A. J. (Corresponding Author)FZJ*

2014
Wiley-Blackwell Oxford [u.a.]

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Please use a persistent id in citations: doi:10.1111/febs.12800

Abstract: Human interleukin (IL)-6 plays a pivotal role in the immune response, hematopoiesis, the acute-phase response, and inflammation. IL-6 has three distinct receptor epitopes, termed sites I, II, and III, that facilitate the formation of a signaling complex. IL-6 signals via a homodimer of glycoprotein 130 (gp130) after initially forming a heterodimer with the nonsignaling a-receptor [IL-6 a-receptor (IL-6R)] via site I. Here, we present the backbone dynamics of apo-IL-6 as determined by analysis of NMR relaxation data with the extended model-free formalism of Lipari and Szabo. To alleviate significant resonance overlap in the HSQC-type spectra, cell-free protein synthesis was used to selectively 15N-label residues, thereby ensuring a complete set of residue-specific dynamics. The calculated order parameters [square of the generalized model-free order parameter (S2)] showed significant conformational heterogeneity among clusters of residues in IL-6. In particular, the N-terminal region of the long AB-loop, which corresponds spatially to one of the gp130 receptor binding epitopes (i.e. site III), experiences substantial fluctuations along the conformation of the main chain (S2 = 0.3–0.8) that are not observed at the other two epitopes or in other cytokines. Thus, we postulate that dynamic properties of the AB-loop are responsible for inhibiting the interaction of IL-6 with gp130 in the absence of the IL-6R, and that binding of IL-6R at site I shifts the dynamic equilibrium to favor interaction with gp130 at site III. In addition, molecular dynamics simulations corroborated the NMR-derived dynamics, and showed that the BC-loop adopts different substates that possibly play a role in facilitating receptor assembly.

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Contributing Institute(s):

1. Strukturbiochemie (ICS-6)

Research Program(s):

1. 453 - Physics of the Cell (POF2-453) (POF2-453)

Appears in the scientific report 2014

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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