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@ARTICLE{Bobby:172104,
      author       = {Bobby, Romel and Robustelli, Paul and Kralicek, Andrew V.
                      and Mobli, Mehdi and King, Glenn F. and Grötzinger, Joachim
                      and Dingley, Andrew J.},
      title        = {{F}unctional implications of large backbone amplitude
                      motions of the glycoprotein 130-binding epitope of
                      interleukin-6},
      journal      = {The FEBS journal},
      volume       = {281},
      number       = {10},
      issn         = {1742-464X},
      address      = {Oxford [u.a.]},
      publisher    = {Wiley-Blackwell},
      reportid     = {FZJ-2014-05647},
      pages        = {2471 - 2483},
      year         = {2014},
      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.},
      cin          = {ICS-6},
      ddc          = {540},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {453 - Physics of the Cell (POF2-453)},
      pid          = {G:(DE-HGF)POF2-453},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000336451900014},
      pubmed       = {pmid:24712547},
      doi          = {10.1111/febs.12800},
      url          = {https://juser.fz-juelich.de/record/172104},
}