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The inhibitory mechanism of a small protein reveals its role in antimicrobial peptide sensing.

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Jiang,  Shan
Department of Systems and Synthetic Microbiology, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

Steup,  Lydia C
Department of Systems and Synthetic Microbiology, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

Kippnich,  Charlotte
Department of Systems and Synthetic Microbiology, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Malengo,  Gabriele
Core Facility Flow Cytometry and Imaging, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Yuan,  Jing       
Department of Systems and Synthetic Microbiology, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Citation

Jiang, S., Steup, L. C., Kippnich, C., Lazaridi, S., Malengo, G., Lemmin, T., et al. (2023). The inhibitory mechanism of a small protein reveals its role in antimicrobial peptide sensing. Proceedings of the National Academy of Sciences of the United States of America, 120(41): e2309607120. doi:10.1073/pnas.2309607120.


Cite as: https://hdl.handle.net/21.11116/0000-000D-C4A9-7
Abstract
A large number of small membrane proteins have been uncovered in bacteria, but their mechanism of action has remained mostly elusive. Here, we investigate the mechanism of a physiologically important small protein, MgrB, which represses the activity of the sensor kinase PhoQ and is widely distributed among enterobacteria. The PhoQ/PhoP two-component system is a master regulator of the bacterial virulence program and interacts with MgrB to modulate bacterial virulence, fitness, and drug resistance. A combination of cross-linking approaches with functional assays and protein dynamic simulations revealed structural rearrangements due to interactions between MgrB and PhoQ near the membrane/periplasm interface and along the transmembrane helices. These interactions induce the movement of the PhoQ catalytic domain and the repression of its activity. Without MgrB, PhoQ appears to be much less sensitive to antimicrobial peptides, including the commonly used C18G. In the presence of MgrB, C18G promotes MgrB to dissociate from PhoQ, thus activating PhoQ via derepression. Our findings reveal the inhibitory mechanism of the small protein MgrB and uncover its importance in antimicrobial peptide sensing.