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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Membrane physical properties influence transmembrane helix formation
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Membrane physical properties influence transmembrane helix formation

机译：膜的物理性质影响跨膜螺旋的形成

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摘要

The pHLIP peptide has three states: (Ⅰ) soluble in aqueous buffer, (Ⅱ) bound to the bilayer surface at neutral pH, and (Ⅲ) inserted as a transmembrane (TM) helix at acidic pH. The membrane insertion of pHLIP at low pH can be used to target the acidic tissues characteristic of different diseases, such as cancer. We find that the α-helix content of state II depends on lipid acyl chain length but not cholesterol, suggesting the helicity of the bound state may be controlled by the bilayer elastic bending modulus. Experiments with the P20G variant show the proline residue in pHLIP reduces the α-helix content of both states Ⅱ and Ⅲ. We also observe that the membrane insertion pKa is influenced by membrane physical properties, following a biphasic pattern similar to the membrane thickness optima observed for the function of eukaryotic membrane proteins. Because tumor cells exhibit altered membrane fluidity, we suggest this might influence pHLIP tumor targeting. We used a cell insertion assay to determine the pKa in live cells, observing that the properties in liposomes held in the more complex plasma membrane. Our results show that the formation of a TM helix is modulated by both the conf ormational propensities of the peptide and the physical properties of the bilayer. These results suggest a physical role for helix-membrane interactions in optimizing the function of more complex TM proteins.
机译：pHLIP肽具有三种状态：（Ⅰ）可溶于水性缓冲液，（Ⅱ）在中性pH下与双层表面结合，和（Ⅲ）在酸性pH下作为跨膜（TM）螺旋插入。在低pH下pHLIP的膜插入可用于靶向不同疾病（例如癌症）的酸性组织。我们发现状态II的α-螺旋含量取决于脂质酰基链的长度，而不取决于胆固醇，这表明结合状态的螺旋度可能受双层弹性弯曲模量的控制。用P20G变体进行的实验表明，pHLIP中的脯氨酸残基降低了状态Ⅱ和Ⅲ的α-螺旋含量。我们还观察到膜插入pKa受膜物理性质的影响，遵循类似于真核膜蛋白功能的最佳膜厚度的双相模式。因为肿瘤细胞表现出改变的膜流动性，我们建议这可能会影响pHLIP肿瘤靶向。我们使用细胞插入测定法来确定活细胞中的pKa，观察到脂质体的特性保留在更复杂的质膜中。我们的结果表明，TM螺旋的形成受到肽的构型倾向和双层物理性质的调节。这些结果表明螺旋-膜相互作用在优化更复杂的TM蛋白功能中的物理作用。

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