Many pathogenic bacteria utilize protein-based nanoreactors called bacterial microcompartments to metabolize diverse nutritional sources. This helps pathogenic organisms thrive in human tissues. The bacterial microcompartment is a specialized organelle composed of enzymes surrounded by a protein shell. To function, compounds to be broken down within the bacterial microcompartment must cross the shell and, likewise, the breakdown products must egress the compartments. The goal of the proposed research is to study and disrupt the protein-protein interactions essential for shell integrity. In parallel, we will characterize the permeability properties of BMC shells, and screen for compounds that interfere with flux across the shells. Collectively these data will provide new knowledge about the structural basis of shell function and provide the foundation for producing therapeutics that disrupt shell assembly and permeability.

Public Health Relevance

Many pathogenic bacteria contain specialized nanoreactors that selectively enable them to derive energy while infecting human tissues. The proposed research aims to understand the structure of these nanoreactors, and how they communicate metabolically with their environment and use this information to disrupt nanoreactor assembly and function. The results of this study will be useful for design of therapeutics that can selectively disrupt formation and function of these nanoreactors in pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI114975-04
Application #
9524398
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Brown, Liliana L
Project Start
2015-01-01
Project End
2022-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Type
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
Plegaria, Jefferson S; Kerfeld, Cheryl A (2018) Engineering nanoreactors using bacterial microcompartment architectures. Curr Opin Biotechnol 51:1-7
Kerfeld, Cheryl A; Aussignargues, Clement; Zarzycki, Jan et al. (2018) Bacterial microcompartments. Nat Rev Microbiol 16:277-290
Hagen, Andrew; Sutter, Markus; Sloan, Nancy et al. (2018) Programmed loading and rapid purification of engineered bacterial microcompartment shells. Nat Commun 9:2881
Hagen, Andrew R; Plegaria, Jefferson S; Sloan, Nancy et al. (2018) In Vitro Assembly of Diverse Bacterial Microcompartment Shell Architectures. Nano Lett 18:7030-7037
Sutter, Markus; Greber, Basil; Aussignargues, Clement et al. (2017) Assembly principles and structure of a 6.5-MDa bacterial microcompartment shell. Science 356:1293-1297
Zarzycki, Jan; Sutter, Markus; Cortina, Niña Socorro et al. (2017) In Vitro Characterization and Concerted Function of Three Core Enzymes of a Glycyl Radical Enzyme - Associated Bacterial Microcompartment. Sci Rep 7:42757
Sutter, Markus; Faulkner, Matthew; Aussignargues, Clément et al. (2016) Visualization of Bacterial Microcompartment Facet Assembly Using High-Speed Atomic Force Microscopy. Nano Lett 16:1590-5
Erbilgin, Onur; Sutter, Markus; Kerfeld, Cheryl A (2016) The Structural Basis of Coenzyme A Recycling in a Bacterial Organelle. PLoS Biol 14:e1002399
Zarzycki, Jan; Erbilgin, Onur; Kerfeld, Cheryl A (2015) Bioinformatic characterization of glycyl radical enzyme-associated bacterial microcompartments. Appl Environ Microbiol 81:8315-29