期刊
CELL CYCLE
卷 7, 期 17, 页码 2667-2673出版社
LANDES BIOSCIENCE
DOI: 10.4161/cc.7.17.6596
关键词
FRET; microdomain; nanocluster; plasma membrane; Ras; structure
类别
资金
- Swiss National Science Foundation [PA00A-111446]
- NHMRC (Australia
- NIH
- Howard Hughes Medical Institute
- National Biomedical Computation Resource
- Accelrys Inc
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.
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