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000172104 0247_ $$2ISSN$$a1742-4658
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000172104 037__ $$aFZJ-2014-05647
000172104 041__ $$aEnglish
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000172104 1001_ $$0P:(DE-HGF)0$$aBobby, Romel$$b0
000172104 245__ $$aFunctional implications of large backbone amplitude motions of the glycoprotein 130-binding epitope of interleukin-6
000172104 260__ $$aOxford [u.a.]$$bWiley-Blackwell$$c2014
000172104 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1415696391_4058
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000172104 520__ $$aHuman 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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000172104 7001_ $$0P:(DE-HGF)0$$aRobustelli, Paul$$b1
000172104 7001_ $$0P:(DE-HGF)0$$aKralicek, Andrew V.$$b2
000172104 7001_ $$0P:(DE-HGF)0$$aMobli, Mehdi$$b3
000172104 7001_ $$0P:(DE-HGF)0$$aKing, Glenn F.$$b4
000172104 7001_ $$0P:(DE-HGF)0$$aGrötzinger, Joachim$$b5
000172104 7001_ $$0P:(DE-HGF)0$$aDingley, Andrew J.$$b6$$eCorresponding Author
000172104 773__ $$0PERI:(DE-600)2172518-4$$a10.1111/febs.12800$$gVol. 281, no. 10, p. 2471 - 2483$$n10$$p2471 - 2483$$tThe @FEBS journal$$v281$$x1742-464X$$y2014
000172104 8564_ $$uhttp://onlinelibrary.wiley.com/doi/10.1111/febs.12800/pdf
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000172104 9141_ $$y2014
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