Predisposition of the dark state of rhodopsin to functional changes in structure

Basak Isin, A. J. Rader, Harpreet Kaur Dhiman, Judith Klein-Seetharaman, Ivet Bahar

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

As the only member of the family of G-protein-coupled receptors for which atomic coordinates are available, rhodopsin is widely studied for insight into the molecular mechanism of G-protein-coupled receptor activation. The currently available structures refer to the inactive, dark state, of rhodopsin, rather than the light-activated metarhodopsin II (Meta II) state. A model for the Meta II state is proposed here by analyzing elastic network normal modes in conjunction with experimental data. Key mechanical features and interactions broken/formed in the proposed model are found to be consistent with the experimental data. The model is further tested by using a set of Meta II fluorescence decay rates measured to empirically characterize the deactivation of rhodopsin mutants. The model is found to correctly predict 93% of the experimentally observed effects in 119 rhodopsin mutants for which the decay rates and misfolding data have been measured, including a systematic analysis of Cys→Ser replacements reported here. Based on the detailed comparison between model and experiments, a cooperative activation mechanism is deduced that couples retinal isomerization to concerted changes in conformation, facilitated by the intrinsic dynamics of rhodopsin. A global hinge site is identified near the retinal-binding pocket that ensures the efficient propagation of signals from the central transmembrane region to both cytoplasmic and extracellular ends. The predicted activation mechanism opens the transmembrane helices at the critical G-protein binding cytoplasmic domain. This model provides a detailed, mechanistic description of the activation process, extending experimental observations and yielding new insights for further tests.

Original languageEnglish (US)
Pages (from-to)970-983
Number of pages14
JournalProteins: Structure, Function and Genetics
Volume65
Issue number4
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

Keywords

  • Collective dynamics
  • Elastic network
  • G-protein-coupled receptors
  • Gaussian network model
  • Light activation
  • Metarhodopsin II
  • Retinal isomerization

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

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