Identification of a Chaperone for the SecA2 Protein Export Pathway of Mycobacterium tuberculosis

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  • March 19, 2019
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  • Miller, Brittany
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The bacterial pathogen Mycobacterium tuberculosis is responsible for the disease tuberculosis. To promote disease, M. tuberculosis exports proteins from the cytoplasm to the bacterial cell surface or out into the host environment. Exported proteins are in an ideal location to manipulate the host. All bacteria, including mycobacteria, utilize the Sec export system for the bulk of protein export. The Sec system is composed of an ATPase protein, SecA, and a membrane channel complex, SecYEG. Mycobacteria, along with some Gram-positive bacteria, contain a second, functionally distinct paralog of the SecA protein. In mycobacteria, the SecA responsible for housekeeping export is called SecA1 and is essential for bacterial survival, while the second SecA is called SecA2 and exports a smaller subset of proteins and is important for M. tuberculosis virulence. The mechanism of SecA2-dependent export is not well understood. Past data support a model where the mycobacterial SecA2 export pathway is integrated into the housekeeping Sec pathway, and SecA2 shares use of the same SecYEG channel as SecA1 to export its substrates. Like SecA1, SecA2 requires ATPase activity to function. In this dissertation, we take the approach of characterizing suppressors of a secA2 mutant allele to better understand the mechanism of SecA2-dependent export. Intragenic suppressor mutations map to the surface of SecA2 and help identify functional regions of SecA2 that may promote interactions with SecYEG, SecA2 substrates or other partners of SecA2. Extragenic suppressor mutations map to a new component of the SecA2 pathway that we named SatS. In M. tuberculosis, SatS is required for the export of a subset of SecA2 substrates and for pathogenesis. SatS functions as a protein export chaperone that protects and promotes export of its specific substrates. Structural studies of SatS reveal a new fold combined with hydrophobic grooves representing potential sites of substrate binding. Taken together, the findings presented in this dissertation advance our understanding of the mechanism of the SecA2 export pathway and expand our appreciation of the diversity among chaperones by identifying SatS as a new type of protein export chaperone.
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  • In Copyright
Advisor
  • Braunstein, Miriam
  • Nicholas, Robert
  • Miller, Virginia
  • Dangl, Jeff
  • Cotter, Peggy
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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