Consortia for High-Throughput-Enabled Structural Biology Partnerships (U01)

高通量结构生物学合作联盟 (U01)

• 批准号: 8149802
• 负责人: Joshua N. Adkins
• 金额: $ 100.75万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8149802
• 关键词: Consortia; Throughput; Enabled; Structural; Biology; Consortia; Throughput; Enabled; Structural; Biology

DESCRIPTION (provided by applicant): While powerful for studying pathogenic secreted effectors, structural biology has not been used to a large extent to study effector-host protein interactions. In this proposal, we use known and novel secreted effectors and an experimental pipeline that will provide broad insights into how a model pathogen, Salmonella, subverts host cell function. Aim 1 simultaneously provides key functional insights into effector protein potency and function using broad set of assays, while at the same time serves as an important selection step to focus structural characterization by the PSI network on the most valuable targets. Aim 2 provides valuable information about the host proteins and protein pathways, using cross-linking and proteomics, that each effector interacts with and provides the PSI network with a prioritized list of host protein targets for structural characterization. Aim 3 interrogates possible specific protein-protein interactions and provides a selection of validated protein-protein interactions and possibly ligands for structural characterization by PSI network. Ultimately, structure-function studies of individual secreted effectors are invaluable to the host-pathogen research community. However, the insights into host-pathogen biology gained from this large parallel characterization effort with multiple effectors will advance understanding at a more complete systems level. PUBLIC HEALTH RELEVANCE: Advanced mass spectrometry methods with structure determinations will allow for improved understanding of the interactions between human host proteins and pathogens; this research may lead to new therapies for infectious diseases. The specific pathogen model to be studied here is Salmonella, a pathogen that has been the cause of a number of significant food-borne outbreaks in recent years.

描述（由申请人提供）：虽然有能力研究致病性分泌效应子，但结构生物学尚未在很大程度上用于研究效应子宿主蛋白相互作用。在此提案中，我们使用已知和新颖的分泌效应子和实验管道，该管道将提供有关模型病原体（沙门氏菌）如何颠覆宿主细胞功能的广泛见解。 AIM 1同时使用广泛的测定集对效应蛋白效力和功能提供关键功能见解，同时，作为重要的选择步骤，将PSI网络集中在最有价值的目标上。 AIM 2使用交联和蛋白质组学提供了有关宿主蛋白质和蛋白质途径的有价值的信息，即每个效应子都与PSI网络相互作用并提供具有结构性表征的宿主蛋白靶标列表的优先列表。 AIM 3询问可能的特定蛋白质 - 蛋白质相互作用，并提供了经过验证的蛋白质 - 蛋白质相互作用以及可能通过PSI网络进行结构表征的配体。最终，单个分泌效应子的结构功能研究对宿主病原研究界来说是宝贵的。但是，从这种庞大的平行表征和多个效应子中获得的对宿主生物生物学的见解将在更完整的系统级别上提高理解。 公共卫生相关性：具有结构确定的高级质谱法可以提高对人宿主蛋白与病原体之间相互作用的了解；这项研究可能导致新的传染病疗法。这里要研究的特定病原体模型是沙门氏菌，这是一种病原体，是近年来造成许多大量食物传播疫情的原因。