A novel protein export chaperone of Mycobacterium tuberculosis

结核分枝杆菌的新型蛋白质输出伴侣

基本信息

批准号：
9892319
负责人：
Miriam S. Braunstein
金额：
$ 59.87万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-03 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892319
关键词：
Antigens Antitubercular Agents Attenuated Live Virus Vaccine Bacterial Physiology Bacterial Proteins Binding Sites Biochemical Biochemical Genetics Biology Categories Cessation of life Complex Crystallization Cytoplasm Data Development Engineering Environment Epidemic Exhibits Future Genetic Structures Genus Mycobacterium Goals Growth Health Hydrophobicity Immune response Infection Interdisciplinary Study Knowledge Label Laboratories Lead Length Lipids Measures Molecular Molecular Biology Molecular Chaperones Mycobacterium tuberculosis Pathogenesis Pathway interactions Peptides Phagosomes Phosphoric Monoester Hydrolases Play Protein Export Pathway Proteins Proteomics Research Personnel Roentgen Rays Role Structure Substrate Specificity Testing Tuberculosis Virulence World Health biological systems biophysical analysis cell envelope drug development extracellular improved macrophage mycobacterial novel novel strategies novel therapeutics pathogenic bacteria prevent stoichiometry tool tuberculosis treatment vaccine development

项目摘要

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), represents a severe world health crisis (4,000 TB deaths daily). A better understanding of Mtb biology and pathogenesis will drive development of novel strategies to control the TB epidemic. In bacterial pathogens, like Mtb, many proteins are exported to the bacterial cell envelope or the extracellular environment in order to carry out critical functions in bacterial physiology, virulence or immune responses. Thus, Mtb pathways that export proteins could be targeted or exploited for the development of novel anti-TB control measures. However, significant gaps exist in our understanding of Mtb protein export. This proposal is to determine the mechanism of SatS, a novel protein export chaperone we discovered in Mtb. SatS is a chaperone for a subset of proteins that are exported by the specialized SecA2 protein export pathway, and SatS is required for intracellular growth of Mtb in macrophages. However, SatS shares no sequence or structural similarity with any previously characterized proteins and the mechanism of SatS is completely unknown. Substrate specificity and the scope of SatS substrates are also unknown. Aim 1 of this proposal is to determine the mechanistic details of SatS function in protein export. Aim 2 is to determine the structures of SatS and that of SatS in complex with peptides of substrates. Aim 3 is to identify SatS-binding sites in substrates and to identify additional SatS substrates. By completing these Aims, we will determine the mechanism and contribution of SatS to Mtb protein export and biology. More broadly, these studies will improve our understanding of bacterial strategies for exporting proteins and of the diversity of molecular chaperones across biological systems. Long-term, the results could lead to strategies for inhibiting protein export as a novel anti-TB therapy. Alternatively, the knowledge gained could be harnessed to engineer mycobacterial strains with improved capacity to export proteins for use as experimental tools or as live, attenuated vaccines with enhanced antigen export.

结核分枝杆菌（MTB），结核病的病因（TB）代表严重的世界健康危机（每天4,000 TB死亡）。更好地了解MTB生物学和发病机理将推动发展控制结核病流行的新型策略。在细菌病原体（如MTB）中，许多蛋白质被导出到为了在细菌中执行关键功能，细菌细胞包膜或细胞外环境生理，毒力或免疫反应。因此，可以针对导出蛋白的MTB途径或利用用于开发新型抗TB控制措施。但是，我们的了解MTB蛋白出口。该建议是确定SAT的机制，SATS是一种新型的蛋白质导出伴侣，我们发现了在MTB中。 SATS是由专门的SECA2蛋白导出的蛋白质子集的伴侣途径和SAT是巨噬细胞中MTB细胞内生长所必需的。但是，SATS no 序列或结构性相似性与任何先前表征的蛋白质以及SAT的机制是完全未知。底物特异性和SATS底物的范围也未知。目标1 建议是确定蛋白质导出中SATS功能的机械细节。目标2是确定 SATS的结构和与底物肽的复杂性。 AIM 3是确定SATS结合基板中的站点并识别其他SATS基板。通过完成这些目标，我们将确定 SATS对MTB蛋白出口和生物学的机制和贡献。更广泛地，这些研究将提高我们对导出蛋白质和分子多样性的细菌策略的理解跨生物系统的伴侣。长期，结果可能导致抑制蛋白质的策略出口作为一种新型的抗TB疗法。另外，获得的知识可能会被利用分枝杆菌菌株具有提高导出蛋白的能力以用作实验工具的能力或实时菌株抗原出口增强的疫苗减弱。