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Structural and functional studies of the Legionella pneumophila dot T4SS

嗜肺军团菌 dot T4SS 的结构和功能研究

基本信息

批准号：
10084702
负责人：
Clarissa Lynn Durie
金额：
$ 6.57万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2020-01-01 至 2021-12-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084702
关键词：
Address Anti-Bacterial Agents Antibiotic Resistance Architecture Bacteria Bartonella Biochemical Bordetella pertussis Brucella Cells Collaborations Complex Coxiella Cryo-electron tomography Cryoelectron Microscopy DNA Data Data Set Defect Escherichia coli Eukaryotic Cell Goals Gram-Negative Bacteria Grant Hand Helicobacter pylori Legionella pneumophila Maps Mass Spectrum Analysis Membrane Microbial Biofilms Modeling Molecular Names Negative Staining Nucleic Acids Oncogenes Organelles Pathogenesis Pilum Plasmids Protein Export Pathway Protein Secretion Proteins Publishing Resolution Rhizobium radiobacter Sampling Structure Substrate Specificity System Titan Toxin Type IV Secretion System Pathway War Work Xanthomonas density extracellular genetic approach global health host colonization human disease in vivo insight molecular modeling mutant particle pathogen pathogenic bacteria periplasm prototype resistance gene three dimensional structure trafficking treatment strategy weapons

项目摘要

Project Abstract Bacterial pathogens are a threat to global health and have evolved elaborate strategies to infect their hosts. One potent bacterial weapon in the war between host and pathogen is the Type IV secretion system (T4SS), found in a wide variety of bacterial species, including those that cause human disease, such as Legionella pneumophila, Helicobacter pylori, Bordetella pertussis, Brucella, Bartonella, and Coxiella. The L. pneumophila, T4SS translocates 100s of effector proteins into the host cell and is essential for pathogenesis. T4SSs are challenging complexes to work with because they span the inner and outer membranes of Gram-negative bacteria and contain a minimum of 12 proteins. Studies in prototype systems, such as E. coli plasmids and A. tumefaciens show that T4SSs are generally organized into an outer membrane core complex (OMCC), an inner membrane complex (IMC), and in some species an extracellular pilus. While there are no published high- resolution (sub-3.5 Å) structures of an entire T4SS; there are sub-3.5 Å structures of OMCCs from both the Xanthomonas citri and conjugation system that translocate DNA. In contrast to the DNA-translocating T4SSs, the L. pneumophila T4SS is composed of ~26 components and low resolution (~30 Å) cryo-electron tomography studies show that this T4SS has an enlarged OMCC and contains periplasmic densities not seen in the structures of minimized E. coli and X. citri T4SSs. The lack of detailed structural information limits our mechanistic understanding of how the L. pneumophila T4SS functions and contributes to pathogenesis. The focus of this proposal is to use a combination of structural and genetic approaches to construct the first detailed molecular map of the organization of the L. pneumophila T4SS. These high resolution models will be used to address fundamental questions such as whether there are conserved structural components shared among T4SSs that can be exploited for new anti-bacterial treatment strategies, how T4SSs are tuned to export proteins versus nucleic acids, and how export of effectors is regulated.

项目摘要