%0 Journal Article
%A Bobby, Romel
%A Robustelli, Paul
%A Kralicek, Andrew V.
%A Mobli, Mehdi
%A King, Glenn F.
%A Grötzinger, Joachim
%A Dingley, Andrew J.
%T Functional implications of large backbone amplitude motions of the glycoprotein 130-binding epitope of interleukin-6
%J The FEBS journal
%V 281
%N 10
%@ 1742-464X
%C Oxford [u.a.]
%I Wiley-Blackwell
%M FZJ-2014-05647
%P 2471 - 2483
%D 2014
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%U <Go to ISI:>//WOS:000336451900014
%$ pmid:24712547
%R 10.1111/febs.12800
%U https://juser.fz-juelich.de/record/172104