Packing of the Extracellular Domain Hydrophobic Core Has Evolved to Facilitate Pentameric Ligand-gated Ion Channel Function
Packing of the Extracellular Domain Hydrophobic Core Has Evolved to Facilitate Pentameric Ligand-gated Ion Channel Function
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DOI：
10.1074/jbc.m110.156851
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发表时间：
2011-02-04
影响因子：
4.8
通讯作者：
Czajkowski, Cynthia
中科院分区：
文献类型：
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作者：
Dellisanti, Cosma D.;Hanson, Sonya M.;Czajkowski, Cynthia
蛋白质的功能取决于构象灵活性和折叠稳定性。疏水核心的松散包装在蛋白质中并不罕见，因为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，我们表明真核五聚体配体门控离子通道的特征是其胞外结构域β -三明治核心的松散包装，并且松散包装有助于它们在配体存在下从封闭通道状态快速切换到开放通道状态的能力。GABA(A)受体的功能分析表明，增加β核包装会破坏GABA介导的电流，损害GABA的功效，减缓GABA电流的激活和脱敏。我们提出疏水β核的松散包装是一种进化策略，旨在促进真核五聚体配体门控离子通道的变构机制。
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 beta-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 beta-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 beta-core developed as an evolutionary strategy aimed to facilitate the allosteric mechanisms of eukaryotic pentameric ligand-gated ion channels.