Abankwa Daniel, Gorfe Alemayehu A, Hancock John F
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
Cell Cycle. 2008 Sep 1;7(17):2667-73. doi: 10.4161/cc.7.17.6596. Epub 2008 Sep 28.
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.
20多年来，了解Ras GTP酶的信号传导功能一直是众多研究的重点。Ras的催化结构域和膜锚定C末端高变区（HVR）对其细胞功能而言都是必需的。然而，尽管高度保守的催化结构域已在原子水平上得到详细表征，但全长膜结合型Ras的结构仍然难以捉摸。缺乏关于全长蛋白的结构知识限制了我们对Ras信号传导的理解。例如，与效应器形成复合物的Ras催化结构域的结构并不能为不同Ras同工型的功能特异性提供依据。最近的分子动力学模拟结合生物物理和细胞生物学实验表明，HVR和G结构域的部分区域与脂质尾部共同作用，将H-Ras锚定到质膜上。在GTP结合状态下，H-Ras采取一种取向，使得Ras效应器能够识别并转化为相应的MAPK信号传导。在此，我们讨论一项分析的细节，该分析提出了一种关于Ras功能的新型平衡模型。该平衡模型使Ras膜取向合理化，并可能有助于解释Ras与其效应器和调节剂的同工型特异性相互作用。
