Details
| Original language | English |
|---|---|
| Pages (from-to) | 510-523 |
| Number of pages | 14 |
| Journal | Genes and Development |
| Volume | 39 |
| Issue number | 7 |
| Publication status | Published - 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
- Medicine(all)
- General Medicine
Sustainable Development Goals
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In: Genes and Development, Vol. 39, No. 7, 14.03.2025, p. 510-523.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
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.
KW - AAA proteases
KW - adaptor
KW - Bacillus subtilis
KW - ClpC
KW - ClpCP
KW - MdfA
KW - protein degradation
KW - sporulation
KW - X-ray crystallography
KW - YjbA
UR - http://www.scopus.com/inward/record.url?scp=105003061515&partnerID=8YFLogxK
U2 - 10.1101/gad.352498.124
DO - 10.1101/gad.352498.124
M3 - Article
C2 - 40086879
AN - SCOPUS:105003061515
VL - 39
SP - 510
EP - 523
JO - Genes and Development
JF - Genes and Development
SN - 0890-9369
IS - 7
ER -