Structure-guided disruption of the pseudopilus tip complex inhibits the Type II secretion in Pseudomonas aeruginosa
| Autor: | Shu Wang, Zongchao Jia, Wenwen Zhang, Frédérick Faucher, Jun Zheng, Keith Poole, Yichen Zhang, Nolan Neville |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Nematoda Protein Conformation Physiology Secretion Systems medicine.disease_cause Crystallography X-Ray Pathology and Laboratory Medicine Biochemistry Microbial Physiology Type II Secretion Systems Medicine and Health Sciences Bacterial Physiology Biology (General) Caenorhabditis elegans Crystallography biology Type II secretion system Virulence Chemistry Physics Pseudomonas Aeruginosa Eukaryota Animal Models Condensed Matter Physics Lipids Transport protein Cell biology Bacterial Pathogens Mutant Strains Experimental Organism Systems Medical Microbiology Caenorhabditis Elegans Physical Sciences Crystal Structure Pathogens Research Article QH301-705.5 Virulence Factors Immunology Research and Analysis Methods Microbiology 03 medical and health sciences Model Organisms Bacterial Proteins Virology Pseudomonas medicine Extracellular Genetics Animals Solid State Physics Secretion Pseudomonas Infections Molecular Biology Microbial Pathogens Bacteria Pseudomonas aeruginosa Organisms Membrane Proteins Biology and Life Sciences Bacteriology Periplasmic space RC581-607 biology.organism_classification Invertebrates 030104 developmental biology Fimbriae Bacterial Mutation Animal Studies Caenorhabditis Parasitology Immunologic diseases. Allergy Physiological Processes |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 14, Iss 10, p e1007343 (2018) |
| ISSN: | 1553-7374 |
| Popis: | Pseudomonas aeruginosa utilizes the Type II secretion system (T2SS) to translocate a wide range of large, structured protein virulence factors through the periplasm to the extracellular environment for infection. In the T2SS, five pseudopilins assemble into the pseudopilus that acts as a piston to extrude exoproteins out of cells. Through structure determination of the pseudopilin complexes of XcpVWX and XcpVW and function analysis, we have confirmed that two minor pseudopilins, XcpV and XcpW, constitute a core complex indispensable to the pseudopilus tip. The absence of either XcpV or -W resulted in the non-functional T2SS. Our small-angle X-ray scattering experiment for the first time revealed the architecture of the entire pseudopilus tip and established the working model. Based on the interaction interface of complexes, we have developed inhibitory peptides. The structure-based peptides not only disrupted of the XcpVW core complex and the entire pseudopilus tip in vitro but also inhibited the T2SS in vivo. More importantly, these peptides effectively reduced the virulence of P. aeruginosa towards Caenorhabditis elegans. Author summary The Type II secretion system has been characterized as an important virulence factor translocation machine that secrets various toxic proteins from the periplasm into the extracellular milieu used by a wide spectrum of Gram-negative bacteria. Through the characterization of the structure of the pseudopilus tip complex by protein crystallography and small-angle X-ray scattering, we have identified a critical interaction interface in the core binary complex formed by two minor pseudopilins, XcpV and–W, in Pseudomonas aeruginosa. Based on the interaction interface, two inhibitory peptides were developed, which showed potency of disrupting the entire pseudopilus tip complex and further inhibited the Type II secretion system. When applied to Caenorhabditis elegans, these peptides prevent the killing of worms by the P. aeruginosa. Our work has represented the first successful research on the inhibition of the Type II secretion system based on the structure of the pseudopilus tip complex. |
| Databáze: | OpenAIRE |
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