Functional implications of large backbone amplitude motions of the glycoprotein 130-binding epitope of interleukin-6

Bobby, Romel, Robustelli, Paul, Kralicek, Andrew V., Mobli, Mehdi, King, Glenn F., Grotzinger, Joachim and Dingley, Andrew J. (2014) Functional implications of large backbone amplitude motions of the glycoprotein 130-binding epitope of interleukin-6. FEBS Journal, 281 10: 2471-2483. doi:10.1111/febs.12800

Author Bobby, Romel
Robustelli, Paul
Kralicek, Andrew V.
Mobli, Mehdi
King, Glenn F.
Grotzinger, Joachim
Dingley, Andrew J.
Title Functional implications of large backbone amplitude motions of the glycoprotein 130-binding epitope of interleukin-6
Journal name FEBS Journal   Check publisher's open access policy
ISSN 1742-4658
Publication date 2014-05-01
Year available 2014
Sub-type Article (original research)
DOI 10.1111/febs.12800
Open Access Status
Volume 281
Issue 10
Start page 2471
End page 2483
Total pages 13
Place of publication Oxford, United Kingdom
Publisher Wiley-Blackwell
Language eng
Formatted 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 α-receptor [IL-6 α-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.
Keyword Biochemistry & Molecular Biology
Biochemistry & Molecular Biology
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 08-UOA-086 BMS
SFB 415
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
Centre for Advanced Imaging Publications
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Citation counts: TR Web of Science Citation Count  Cited 4 times in Thomson Reuters Web of Science Article | Citations
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Created: Thu, 22 May 2014, 21:10:14 EST by Sandrine Ducrot on behalf of Centre for Advanced Imaging