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Proceedings of the National Academy of Sciences of the United States of America
10 10, 2023;120 (41): e2309607120.

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

Shan Jiang, Lydia C Steup, Charlotte Kippnich, Symela Lazaridi, Gabriele Malengo, Thomas Lemmin, Jing Yuan
Author Information
  1. Shan Jiang: Max Planck Institute for Terrestrial Microbiology, 35043 Marburg, Germany. ORCID
  2. Lydia C Steup: Max Planck Institute for Terrestrial Microbiology, 35043 Marburg, Germany.
  3. Charlotte Kippnich: Max Planck Institute for Terrestrial Microbiology, 35043 Marburg, Germany.
  4. Symela Lazaridi: Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, 3012 Bern, Switzerland.
  5. Gabriele Malengo: Max Planck Institute for Terrestrial Microbiology, 35043 Marburg, Germany.
  6. Thomas Lemmin: Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, 3012 Bern, Switzerland. ORCID
  7. Jing Yuan: Max Planck Institute for Terrestrial Microbiology, 35043 Marburg, Germany. ORCID
PMID: 37792514 DOI: 10.1073/pnas.2309607120

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.

Keywords

antimicrobial peptide bacteria signaling sensor kinase small protein two-component system

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MeSH Term

Bacterial Proteins
Antimicrobial Peptides
Membrane Proteins
Periplasm
Gene Expression Regulation, Bacterial

Chemicals

Bacterial Proteins
Antimicrobial Peptides
Membrane Proteins
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 31

Word Cloud

Created with Highcharts 10.0.0MgrBPhoQsmallproteinmechanismantimicrobialpeptidebacteriaactivitysensorkinasetwo-componentsystembacterialvirulenceinteractionsC18GinhibitorysensinglargenumbermembraneproteinsuncoveredactionremainedmostlyelusiveinvestigatephysiologicallyimportantrepresseswidelydistributedamongenterobacteriaPhoQ/PhoPmasterregulatorprograminteractsmodulatefitnessdrugresistancecombinationcross-linkingapproachesfunctionalassaysdynamicsimulationsrevealedstructuralrearrangementsduenearmembrane/periplasminterfacealongtransmembranehelicesinducemovementcatalyticdomainrepressionWithoutappearsmuchlesssensitivepeptidesincludingcommonlyusedpresencepromotesdissociatethusactivatingviaderepressionfindingsrevealuncoverimportancerevealsrolesignaling

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