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Cell Cycle. 2008 Sep 1;7(17):2667-73. Epub 2008 Sep 28.

Mechanisms of Ras membrane organization and signalling: Ras on a rocker.

Author information

  • 1Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia. d.abankwa@imb.uq.edu.au

Abstract

Understanding the signalling function of Ras GTPases has been the focus of much research for over 20 years. Both the catalytic domain and the membrane anchoring C terminal hypervariable region (HVR) of Ras are necessary for its cellular function. However, while the highly conserved catalytic domain has been characterized in atomic detail, the structure of the full-length membrane-bound Ras has remained elusive. Lack of structural knowledge on the full-length protein limited our understanding of Ras signalling. For example, structures of the Ras catalytic domain solved in complex with effectors do not provide a basis for the functional specificity of different Ras isoforms. Recent molecular dynamics simulations in combination with biophysical and cell biological experiments have shown that the HVR and parts of the G domain cofunction with the lipid tails to anchor H-ras to the plasma membrane. In the GTP-bound state, H-ras adopts an orientation that allows read out by Ras effectors and translation into corresponding MAPK signalling. Here we discuss details of an analysis that suggests a novel balance model for Ras functioning. The balance model rationalizes Ras membrane orientation and may help explain isoform specific interactions of Ras with its effectors and modulators.

PMID:
18758236
[PubMed - indexed for MEDLINE]
PMCID:
PMC2782589
Free PMC Article

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