Structure and interactions of the Voltage-Dependent Anion Channel(VDAC)

电压依赖性阴离子通道（VDAC）的结构和相互作用

• 批准号: 8306791
• 负责人: GERHARD WAGNER
• 金额: $ 27.89万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-23 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306791
• 关键词: Address; Amaze; Apoptosis; Apoptotic; Architecture; Bacterial Proteins; Binding; Chemicals; Communicable Diseases; Complex; Detergents; Environment; Family; Funding; Goals; Grant; Human; Infection; Integral Membrane Protein; Ions; Lead; Link; Maps; Measurement; Measures; Mediating; Membrane; Membrane Proteins; Methods; Micelles; Mitochondria; Molecular Conformation; N-terminal; Neisseria; Nuclear; Outer Mitochondrial Membrane; Pattern; Phospholipids; Play; PorB porin; Positioning Attribute; Preparation; Procedures; Process; Production; Protein Isoforms; Proteins; Relaxation; Reporting; Research; Residual state; Role; Solutions; Structure; Testing; Voltage-Dependent Anion Channel; Voltage-Dependent_Anion_Channel-1; antitumor agent; bak protein; cytochrome c; dodecyldimethylamine oxide; erastin; human AMID protein; inhibitor/antagonist; insight; member; nanodisk; pathogen; pathogenic bacteria; porin; protein structure; public health relevance; reconstitution; research study; response; small molecule; structural biology; trafficking; voltage-dependent anion channel 2

DESCRIPTION (provided by applicant): The voltage-dependent anion channel (VDAC) mediates trafficking of small molecules and ions across the eukaryotic outer mitochondrial membrane. There are three isoforms that have distinct reported interactions with small molecules and proteins. These include pro- and anti-apoptotic members of the Bcl-2 family, and the different isoforms of VDAC have been implied to play roles in apoptosis, such as formation or inhibition of the mitochondrial exit channel. Recently, we obtained NMR assignments and determined the solution structure of human VDAC-1 in detergent micelles (Hiller et al., 2008). VDAC has been known for thirty years and numerous reports of interactions and functional aspects have been reported. With the recent NMR characterization of VDAC-1 we are now in a position to validate these reports and elucidate the function of the channel. The goal of the proposed research is to study the structure, interactions and function of VDAC isoforms. We will pursue the following specific aims: 1. Compare structure and interactions of VDAC-1 in LDAO micelles and phospholipids nanodiscs to assess differences between micelle and bilayer environments. 2. Determine the structure of VDAC-2, which contains an N-terminal extension and has reported functions distinct from VDAC-1. 3. Determine the membrane/micelle-bound structures of Bcl-2 type proteins and study VDAC complexes. 4. Characterize complexes of VDAC with the porin PorB from pathogenic bacteria. PUBLIC HEALTH RELEVANCE: We will study the solution structure of the human voltage-dependent anion channel (VDAC) in the membrane mimicking phospholipids nanodiscs and compare it with our recent structure obtained in LDAO micelles. We will also determine the structure of the VDAC-2 isoform, which has been shown to stabilize an inactive form of the Bak protein and may play a crucial role in controlling the onset of apoptosis. We also will investigate interactions of VDAC with Bcl-2-type proteins, bacterial pathogens and small molecules.

描述（由申请人提供）：电压依赖性阴离子通道（VDAC）介导小分子和离子穿过真核细胞线粒体外膜的运输。有三种亚型与小分子和蛋白质具有不同的相互作用。这些包括Bcl-2家族的促凋亡和抗凋亡成员，并且VDAC的不同同种型已经暗示在凋亡中发挥作用，例如线粒体出口通道的形成或抑制。最近，我们获得了NMR分配并确定了人VDAC-1在洗涤剂胶束中的溶液结构（Hiller等人，2008年）。VDAC已被称为三十年，并且已经报道了许多关于相互作用和功能方面的报告。随着最近VDAC-1的NMR表征，我们现在能够验证这些报告并阐明通道的功能。 该研究的目的是研究VDAC异构体的结构、相互作用和功能。我们将努力实现以下具体目标：1.比较VDAC-1在LDAO胶束和磷脂纳米盘中的结构和相互作用，以评估胶束和双层环境之间的差异。2.确定VDAC-2的结构，其包含N-末端延伸，并且具有不同于VDAC-1的报告功能。3.确定Bcl-2型蛋白的膜/胶束结合结构并研究VDAC复合物。4.表征VDAC与来自病原菌的孔蛋白PorB的复合物。 公共卫生相关性：我们将研究人类电压依赖性阴离子通道（VDAC）在膜模拟磷脂纳米盘的溶液结构，并将其与我们最近在LDAO胶束中获得的结构进行比较。我们还将确定VDAC-2亚型的结构，该亚型已被证明可以稳定巴克蛋白的非活性形式，并可能在控制细胞凋亡的发生中起关键作用。我们还将研究VDAC与Bcl-2型蛋白、细菌病原体和小分子的相互作用。