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@ARTICLE{Kirchberg:19450,
      author       = {Kirchberg, K. and Kim, T.Y. and Möller, M. and Skegro, D.
                      and Raju, G.D. and Granzin, J. and Büldt, G. and
                      Schlesinger, R. and Alexiev, U.},
      title        = {{C}onformational dynamics of helix 8 in the {GPCR}
                      rhodopsin controls arrestin activation in the
                      desensitization process},
      journal      = {Proceedings of the National Academy of Sciences of the
                      United States of America},
      volume       = {108},
      issn         = {0027-8424},
      address      = {Washington, DC},
      publisher    = {Academy},
      reportid     = {PreJuSER-19450},
      pages        = {18690 - 18695},
      year         = {2011},
      note         = {We thank Dr. R. Batra Safferling (ICS) and C. Seidler (FU
                      Berlin) for help with sample and measurements, and S.
                      Lehmann for building up the light-scattering instrument. The
                      work was supported by the Deutsche Forschungsgemeinschaft,
                      Sfb 449, (to U.A.) and ONEXIM (to G.B.).},
      abstract     = {Arrestins are regulatory molecules for G-protein coupled
                      receptor function. In visual rhodopsin, selective binding of
                      arrestin to the cytoplasmic side of light-activated,
                      phosphorylated rhodopsin (P-Rh*) terminates signaling via
                      the G-protein transducin. While the "phosphate-sensor" of
                      arrestin for the recognition of receptor-attached phosphates
                      is identified, the molecular mechanism of arrestin binding
                      and the involvement of receptor conformations in this
                      process are still largely hypothetic. Here we used
                      fluorescence pump-probe and time-resolved fluorescence
                      depolarization measurements to investigate the kinetics of
                      arrestin conformational changes and the corresponding
                      nanosecond dynamical changes at the receptor surface. We
                      show that at least two sequential conformational changes of
                      arrestin occur upon interaction with P-Rh*, thus providing a
                      kinetic proof for the suggested multistep nature of arrestin
                      binding. At the cytoplasmic surface of P-Rh*, the structural
                      dynamics of the amphipathic helix 8 (H8), connecting
                      transmembrane helix 7 and the phosphorylated C-terminal
                      tail, depends on the arrestin interaction state. We find
                      that a high mobility of H8 is required in the low-affinity
                      (prebinding) but not in the high-affinity binding state.
                      High-affinity arrestin binding is inhibited when a bulky,
                      inflexible group is bound to H8, indicating close
                      interaction. We further show that this close steric
                      interaction of H8 with arrestin is mandatory for the
                      transition from prebinding to high-affinity binding; i.e.,
                      for arrestin activation. This finding implies a regulatory
                      role for H8 in activation of visual arrestin, which shows
                      high selectivity to P-Rh* in contrast to the broad receptor
                      specificity displayed by the two nonvisual arrestins.},
      keywords     = {Animals / Anisotropy / Arrestin: chemistry / Cattle /
                      Crystallography, X-Ray: methods / Kinetics / Microscopy,
                      Fluorescence: methods / Molecular Conformation /
                      Phosphorylation / Protein Binding / Protein Conformation /
                      Protein Structure, Tertiary / Receptors, G-Protein-Coupled:
                      chemistry / Retina: metabolism / Rhodopsin: chemistry /
                      Signal Transduction / Spectrophotometry: methods / Arrestin
                      (NLM Chemicals) / Receptors, G-Protein-Coupled (NLM
                      Chemicals) / Rhodopsin (NLM Chemicals) / J (WoSType)},
      cin          = {ICS-5 / ICS-6},
      ddc          = {000},
      cid          = {I:(DE-Juel1)ICS-5-20110106 / I:(DE-Juel1)ICS-6-20110106},
      pnm          = {BioSoft: Makromolekulare Systeme und biologische
                      Informationsverarbeitung},
      pid          = {G:(DE-Juel1)FUEK505},
      shelfmark    = {Multidisciplinary Sciences},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:22039220},
      pmc          = {pmc:PMC3219140},
      UT           = {WOS:000297008900034},
      doi          = {10.1073/pnas.1015461108},
      url          = {https://juser.fz-juelich.de/record/19450},
}