A Highly Tilted Membrane Configuration for the Prefusion State of Synaptobrevin
A Highly Tilted Membrane Configuration for the Prefusion State of Synaptobrevin
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DOI：
10.1016/j.bpj.2014.09.013
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发表时间：
2014-11-04
影响因子：
3.4
通讯作者：
Tajkhorshid, Emad
中科院分区：
文献类型：
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作者：
Blanchard, Andrew E.;Arcario, Mark J.;Tajkhorshid, Emad
SNARE复合物在神经元胞吐过程中产生的囊泡融合中起重要作用。调控SNARE复合物形成和最终融合的关键成分是囊泡相关蛋白synaptobrevin的跨膜和连接区域。然而，synaptobrevin在融合前状态下的膜嵌入结构在很大程度上是未知的，这决定了它在融合过程中与其他SNARE蛋白的相互作用。本研究报告了突触brevin在脂质双分子层中的预融合构型的全原子分子动力学模拟，旨在表征蛋白质在膜中的插入深度和方向，以及决定这些特性的氨基酸的性质。通过表征野生型和突变型synaptobrevin的结构特性，确定了c末端添加物对膜包埋synaptobrevin的倾角和插入深度的影响。模拟结果表明，膜嵌入synaptobrevin具有一个强大的、高度倾斜的状态，在跨膜和连接体区域之间具有螺旋连接，从而对预融合synaptobrevin的结构元素进行了明显的新表征，并为解释过去的突变实验提供了一个框架。
The SNARE complex plays a vital role in vesicle fusion arising during neuronal exocytosis. Key components in the regulation of SNARE complex formation, and ultimately fusion, are the transmembrane and linker regions of the vesicle-associated protein, synaptobrevin. However, the membrane-embedded structure of synaptobrevin in its prefusion state, which determines its interaction with other SNARE proteins during fusion, is largely unknown. This study reports all-atom molecular-dynamics simulations of the prefusion configuration of synaptobrevin in a lipid bilayer, aimed at characterizing the insertion depth and the orientation of the protein in the membrane, as well as the nature of the amino acids involved in determining these properties. By characterizing the structural properties of both wild-type and mutant synaptobrevin, the effects of C-terminal additions on tilt and insertion depth of membrane-embedded synaptobrevin are determined. The simulations suggest a robust, highly tilted state for membrane-embedded synaptobrevin with a helical connection between the transmembrane and linker regions, leading to an apparently new characterization of structural elements in prefusion synaptobrevin and providing a framework for interpreting past mutation experiments.