ArticleProceedings of the National Academy of Sciences of the United States of America2016
Reconstitution of a Mycobacterium tuberculosis proteostasis network highlights essential cofactor interactions with chaperone DnaK.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 50 citations in OpenAlex.
- Sec and Tat Mediated Secretion Safeguards Mycobacterium tuberculosis Membrane Homeostasis.Molecular & cellular proteomics : MCP · 2026Article
- HtpG-A Major Virulence Factor and a Promising Vaccine Antigen againstBiomolecules · 2024Review
- Structure of the M. tuberculosis DnaK-GrpE complex reveals how key DnaK roles are controlled.Nature communications · 2024Article
- Understanding ATP Binding to DosS Catalytic Domain with a Short ATP-Lid.Biochemistry · 2023Article
- Peptide-based molecules for the disruption of bacterial Hsp70 chaperones.Current opinion in chemical biology · 2023Review
- HtpG Is a Metal-Dependent Chaperone Which Assists the DnaK/DnaJ/GrpE Chaperone System of Mycobacterium tuberculosis via Direct Association with DnaJ2.Microbiology spectrum · 2023Article
- Comparative genomic analysis reveals differential genomic characteristics and featured genes between rapid- and slow-growingFrontiers in microbiology · 2023Article
- Complementary protocols to evaluate inhibitors against the DnaK chaperone network.STAR protocols · 2022Article
- An allosteric inhibitor of bacterial Hsp70 chaperone potentiates antibiotics and mitigates resistance.Cell chemical biology · 2022Article
- Transcriptomic Analysis of the Dual Response of Rhodococcus aetherivorans BCP1 to Inorganic Arsenic Oxyanions.Applied and environmental microbiology · 2022Article
- Oxidative damage and delayed replication allow viableScience translational medicine · 2021Article
- Recent Insights into the Structure and Function of Mycobacterial Membrane Proteins Facilitated by Cryo-EM.The Journal of membrane biology · 2021Review
- Structural basis for aggregate dissolution and refolding by the Mycobacterium tuberculosis ClpB-DnaK bi-chaperone system.Cell reports · 2021Article
- Article
- Nonredundant functions of Mycobacterium tuberculosis chaperones promote survival under stress.Molecular microbiology · 2021Article
- Article
- The unfoldase ClpC1 ofThe Journal of biological chemistry · 2020Article
- Activity-Based Protein Profiling Reveals That Cephalosporins Selectively Active on Non-replicatingFrontiers in microbiology · 2020Article
- Role of ClpB FromFrontiers in microbiology · 2020Article
- Dual RNA-Seq of Human Leprosy Lesions Identifies Bacterial Determinants Linked to Host Immune Response.Cell reports · 2019Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
During host infection, Mycobacterium tuberculosis (Mtb) encounters several types of stress that impair protein integrity, including reactive oxygen and nitrogen species and chemotherapy. The resulting protein aggregates can be resolved or degraded by molecular machinery conserved from bacteria to eukaryotes. Eukaryotic Hsp104/Hsp70 and their bacterial homologs ClpB/DnaK are ATP-powered chaperones that restore toxic protein aggregates to a native folded state. DnaK is essential in Mycobacterium smegmatis, and ClpB is involved in asymmetrically distributing damaged proteins during cell division as a mechanism of survival in Mtb, commending both proteins as potential drug targets. However, their molecular partners in protein reactivation have not been characterized in mycobacteria. Here, we reconstituted the activities of the Mtb ClpB/DnaK bichaperone system with the cofactors DnaJ1, DnaJ2, and GrpE and the small heat shock protein Hsp20. We found that DnaJ1 and DnaJ2 activate the ATPase activity of DnaK differently. A point mutation in the highly conserved HPD motif of the DnaJ proteins abrogates their ability to activate DnaK, although the DnaJ2 mutant still binds to DnaK. The purified Mtb ClpB/DnaK system reactivated a heat-denatured model substrate, but the DnaJ HPD mutants inhibited the reaction. Finally, either DnaJ1 or DnaJ2 is required for mycobacterial viability, as is the DnaK-activating activity of a DnaJ protein. These studies lay the groundwork for strategies to target essential chaperone-protein interactions in Mtb, the leading cause of death from a bacterial infection.
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