Department of Physiology, University of Wisconsin, Madison, Wisconsin 53711, USA.
J Biol Chem. 2011 Feb 4;286(5):3658-70. doi: 10.1074/jbc.M110.156851. Epub 2010 Nov 22.
Protein function depends on conformational flexibility and folding stability. Loose packing of hydrophobic cores is not infrequent in proteins, as the enhanced flexibility likely contributes to their biological function. Here, using experimental and computational approaches, we show that eukaryotic pentameric ligand-gated ion channels are characterized by loose packing of their extracellular domain β-sandwich cores, and that loose packing contributes to their ability to rapidly switch from closed to open channel states in the presence of ligand. Functional analyses of GABA(A) receptors show that increasing the β-core packing disrupted GABA-mediated currents, with impaired GABA efficacy and slowed GABA current activation and desensitization. We propose that loose packing of the hydrophobic β-core developed as an evolutionary strategy aimed to facilitate the allosteric mechanisms of eukaryotic pentameric ligand-gated ion channels.
蛋白质的功能取决于构象的灵活性和折叠的稳定性。在蛋白质中，疏水性核心的松散堆积并不罕见，因为这种增强的灵活性可能有助于它们的生物学功能。在这里，我们使用实验和计算方法表明，真核五聚体配体门控离子通道的特征是其细胞外结构域β-夹层核心的松散堆积，并且松散堆积有助于它们在配体存在下从关闭状态快速切换到开放通道状态的能力。对 GABA(A)受体的功能分析表明，增加β-核心堆积会破坏 GABA 介导的电流，从而降低 GABA 的功效并减缓 GABA 电流的激活和脱敏。我们提出，疏水性β-核心的松散堆积是一种进化策略，旨在促进真核五聚体配体门控离子通道的变构机制。
