A novel protein export chaperone of Mycobacterium tuberculosis

结核分枝杆菌（Mycobacterium tuberculosis，Mtb）是结核病（TB）的病原体，是严重的世界性健康问题 危机（每天4,000例结核病死亡）。更好地了解结核分枝杆菌生物学和发病机制将推动发展 控制结核病流行的新策略。在细菌病原体中，如Mtb，许多蛋白质被输出到 细菌细胞被膜或细胞外环境，以便在细菌中执行关键功能。 生理学、毒力或免疫反应。因此，输出蛋白质的Mtb途径可以被靶向或 用于开发新的抗结核病控制措施。然而，在我们的国家中存在着巨大的差距。 了解结核分枝杆菌蛋白输出。 本研究的目的是确定SatS的作用机制，SatS是我们发现的一种新的蛋白质输出分子伴侣 在Mtb。SatS是一个伴侣蛋白的一个子集，是由专门的SecA 2蛋白输出 SatS是巨噬细胞中Mtb细胞内生长所必需的。然而，SatS没有 与任何先前表征的蛋白质的序列或结构相似性，并且SatS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SatS在蛋白质输出中功能的机制细节。目标2是确定 SatS的结构以及SatS与底物肽的复合物的结构。目的3是鉴定SatS结合 位点，并确定额外的SatS底物。通过完成这些目标，我们将确定 SatS对Mtb蛋白输出和生物学的作用机制。更广泛地说，这些研究将 提高我们对细菌输出蛋白质的策略和分子多样性的理解， 生物系统中的伴侣。从长远来看，这些结果可能会导致抑制蛋白质的策略， 作为一种新的抗结核治疗出口。或者，所获得的知识可以用于工程 具有改进的输出蛋白质的能力的分枝杆菌菌株用作实验工具或作为活的， 具有增强的抗原输出的减毒疫苗。

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.