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MdfA is a novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore

Research output: Contribution to journalArticleResearchpeer review

Authors

  • Shawn C. Massoni
  • Nicola J. Evans
  • Ingo Hantke
  • Colleen Fenton
  • Kürsa Turgay

Research Organisations

External Research Organisations

  • Mount Holyoke College
  • King's College London
  • University of Durham
  • Max Planck Unit for the Science of Pathogens (MPUSP)

Details

Original languageEnglish
Pages (from-to)510-523
Number of pages14
JournalGenes and Development
Volume39
Issue number7
Publication statusPublished - 14 Mar 2025

Abstract

Bacterial protein degradation machinery consists of chaperone–protease complexes that play vital roles in bacterial growth and development and have sparked interest as novel antimicrobial targets. ClpC–ClpP (ClpCP) is one such chaperone–protease complex, recruited by adaptors to specific functions in the model bacterium Bacillus subtilis and other Gram-positive bacteria, including the pathogens Staphylococcus aureus and Mycobacterium tuberculosis. Here we have identified a new ClpCP adaptor protein, MdfA (metabolic differentiation factor A; formerly YjbA), in a genetic screen for factors that help drive B. subtilis toward metabolic dormancy during spore formation. A knockout of mdfA stimulates gene expression in the developing spore, while aberrant expression of mdfA during vegetative growth is toxic. MdfA binds directly to ClpC to induce its oligomerization and ATPase activity, and this interaction is required for the in vivo effects of mdfA. Finally, a cocrystal structure reveals that MdfA binds to the ClpC N-terminal domain at a location analogous to that on the M. tuberculosis ClpC1 protein where bactericidal cyclic peptides bind. Altogether, our data and that of an accompanying study by Riley and colleagues support a model in which MdfA induces ClpCP-mediated degradation of metabolic enzymes in the developing spore, helping drive it toward metabolic dormancy.

Keywords

    AAA proteases, adaptor, Bacillus subtilis, ClpC, ClpCP, MdfA, protein degradation, sporulation, X-ray crystallography, YjbA

ASJC Scopus subject areas

Sustainable Development Goals

Cite this

MdfA is a novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore. / Massoni, Shawn C.; Evans, Nicola J.; Hantke, Ingo et al.
In: Genes and Development, Vol. 39, No. 7, 14.03.2025, p. 510-523.

Research output: Contribution to journalArticleResearchpeer review

Massoni, SC, Evans, NJ, Hantke, I, Fenton, C, Torpey, JH, Collins, KM, Krysztofinska, EM, Muench, JH, Thapaliya, A, Martínez-Lumbreras, S, Ferrell, SH, Slater, C, Wang, X, Fekade, R, Obwar, S, Yin, S, Vazquez, A, Prior, CB, Turgay, K, Isaacson, RL & Camp, AH 2025, 'MdfA is a novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore', Genes and Development, vol. 39, no. 7, pp. 510-523. https://doi.org/10.1101/gad.352498.124
Massoni, S. C., Evans, N. J., Hantke, I., Fenton, C., Torpey, J. H., Collins, K. M., Krysztofinska, E. M., Muench, J. H., Thapaliya, A., Martínez-Lumbreras, S., Ferrell, S. H., Slater, C., Wang, X., Fekade, R., Obwar, S., Yin, S., Vazquez, A., Prior, C. B., Turgay, K., ... Camp, A. H. (2025). MdfA is a novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore. Genes and Development, 39(7), 510-523. https://doi.org/10.1101/gad.352498.124
Massoni SC, Evans NJ, Hantke I, Fenton C, Torpey JH, Collins KM et al. MdfA is a novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore. Genes and Development. 2025 Mar 14;39(7):510-523. doi: 10.1101/gad.352498.124
Massoni, Shawn C. ; Evans, Nicola J. ; Hantke, Ingo et al. / MdfA is a novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore. In: Genes and Development. 2025 ; Vol. 39, No. 7. pp. 510-523.
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title = "MdfA is a novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore",
abstract = "Bacterial protein degradation machinery consists of chaperone–protease complexes that play vital roles in bacterial growth and development and have sparked interest as novel antimicrobial targets. ClpC–ClpP (ClpCP) is one such chaperone–protease complex, recruited by adaptors to specific functions in the model bacterium Bacillus subtilis and other Gram-positive bacteria, including the pathogens Staphylococcus aureus and Mycobacterium tuberculosis. Here we have identified a new ClpCP adaptor protein, MdfA (metabolic differentiation factor A; formerly YjbA), in a genetic screen for factors that help drive B. subtilis toward metabolic dormancy during spore formation. A knockout of mdfA stimulates gene expression in the developing spore, while aberrant expression of mdfA during vegetative growth is toxic. MdfA binds directly to ClpC to induce its oligomerization and ATPase activity, and this interaction is required for the in vivo effects of mdfA. Finally, a cocrystal structure reveals that MdfA binds to the ClpC N-terminal domain at a location analogous to that on the M. tuberculosis ClpC1 protein where bactericidal cyclic peptides bind. Altogether, our data and that of an accompanying study by Riley and colleagues support a model in which MdfA induces ClpCP-mediated degradation of metabolic enzymes in the developing spore, helping drive it toward metabolic dormancy.",
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T1 - MdfA is a novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore

AU - Massoni, Shawn C.

AU - Evans, Nicola J.

AU - Hantke, Ingo

AU - Fenton, Colleen

AU - Torpey, James H.

AU - Collins, Katherine M.

AU - Krysztofinska, Ewelina M.

AU - Muench, Janina H.

AU - Thapaliya, Arjun

AU - Martínez-Lumbreras, Santiago

AU - Ferrell, Sé Hart

AU - Slater, Celia

AU - Wang, Xinyue

AU - Fekade, Ruth

AU - Obwar, Sandra

AU - Yin, Siyu

AU - Vazquez, Alishba

AU - Prior, Christopher B.

AU - Turgay, Kürsa

AU - Isaacson, Rivka L.

AU - Camp, Amy H.

N1 - Publisher Copyright: © 2025 Massoni et al.

PY - 2025/3/14

Y1 - 2025/3/14

N2 - Bacterial protein degradation machinery consists of chaperone–protease complexes that play vital roles in bacterial growth and development and have sparked interest as novel antimicrobial targets. ClpC–ClpP (ClpCP) is one such chaperone–protease complex, recruited by adaptors to specific functions in the model bacterium Bacillus subtilis and other Gram-positive bacteria, including the pathogens Staphylococcus aureus and Mycobacterium tuberculosis. Here we have identified a new ClpCP adaptor protein, MdfA (metabolic differentiation factor A; formerly YjbA), in a genetic screen for factors that help drive B. subtilis toward metabolic dormancy during spore formation. A knockout of mdfA stimulates gene expression in the developing spore, while aberrant expression of mdfA during vegetative growth is toxic. MdfA binds directly to ClpC to induce its oligomerization and ATPase activity, and this interaction is required for the in vivo effects of mdfA. Finally, a cocrystal structure reveals that MdfA binds to the ClpC N-terminal domain at a location analogous to that on the M. tuberculosis ClpC1 protein where bactericidal cyclic peptides bind. Altogether, our data and that of an accompanying study by Riley and colleagues support a model in which MdfA induces ClpCP-mediated degradation of metabolic enzymes in the developing spore, helping drive it toward metabolic dormancy.

AB - Bacterial protein degradation machinery consists of chaperone–protease complexes that play vital roles in bacterial growth and development and have sparked interest as novel antimicrobial targets. ClpC–ClpP (ClpCP) is one such chaperone–protease complex, recruited by adaptors to specific functions in the model bacterium Bacillus subtilis and other Gram-positive bacteria, including the pathogens Staphylococcus aureus and Mycobacterium tuberculosis. Here we have identified a new ClpCP adaptor protein, MdfA (metabolic differentiation factor A; formerly YjbA), in a genetic screen for factors that help drive B. subtilis toward metabolic dormancy during spore formation. A knockout of mdfA stimulates gene expression in the developing spore, while aberrant expression of mdfA during vegetative growth is toxic. MdfA binds directly to ClpC to induce its oligomerization and ATPase activity, and this interaction is required for the in vivo effects of mdfA. Finally, a cocrystal structure reveals that MdfA binds to the ClpC N-terminal domain at a location analogous to that on the M. tuberculosis ClpC1 protein where bactericidal cyclic peptides bind. Altogether, our data and that of an accompanying study by Riley and colleagues support a model in which MdfA induces ClpCP-mediated degradation of metabolic enzymes in the developing spore, helping drive it toward metabolic dormancy.

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KW - adaptor

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KW - ClpC

KW - ClpCP

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KW - protein degradation

KW - sporulation

KW - X-ray crystallography

KW - YjbA

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DO - 10.1101/gad.352498.124

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