ArticleProceedings of the National Academy of Sciences of the United States of America2020
Modular and coordinated activity of AAA+ active sites in the double-ring ClpA unfoldase of the ClpAP protease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 16 citations in OpenAlex.
- Targeting ClpP Protease: Emerging Therapeutic Strategies and Small-Molecule Modulators in Drug Discovery.Medicinal research reviews · 2026Review
- Molecular mechanisms of mitochondrial AAA+ proteases.The Journal of biological chemistry · 2026Review
- Substrate-dependent activation of LONP1 informs on proteolytic regulation and ATPase motor function.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Allosteric regulation of proteolytic machines unveiled by the synergy between cryo-EM and solution NMR spectroscopy.The Biochemical journal · 2025Review
- How the double-ring ClpAP protease motor grips the substrate to unfold and degrade stable proteins.The Journal of biological chemistry · 2024Article
- Structural and mechanistic studies on human LONP1 redefine the hand-over-hand translocation mechanism.bioRxiv : the preprint server for biology · 2024Article
- Deciphering the mechanism and function of Hsp100 unfoldases from protein structure.Biochemical Society transactions · 2022Article
- AAA+ protease-adaptor structures reveal altered conformations and ring specialization.Nature structural & molecular biology · 2022Article
- FtsH degrades dihydrofolate reductase by recognizing a partially folded species.Protein science : a publication of the Protein Society · 2022Article
- Ultrafast pore-loop dynamics in a AAA+ machine point to a Brownian-ratchet mechanism for protein translocation.Science advances · 2021Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
ClpA is a hexameric double-ring AAA+ unfoldase/translocase that functions with the ClpP peptidase to degrade proteins that are damaged or unneeded. How the 12 ATPase active sites of ClpA, 6 in the D1 ring and 6 in the D2 ring, work together to fuel ATP-dependent degradation is not understood. We use site-specific cross-linking to engineer ClpA hexamers with alternating ATPase-active and ATPase-inactive modules in the D1 ring, the D2 ring, or both rings to determine if these active sites function together. Our results demonstrate that D2 modules coordinate with D1 modules and ClpP during mechanical work. However, there is no requirement for adjacent modules in either ring to be active for efficient enzyme function. Notably, ClpAP variants with just three alternating active D2 modules are robust protein translocases and function with double the energetic efficiency of ClpAP variants with completely active D2 rings. Although D2 is the more powerful motor, three or six active D1 modules are important for high enzyme processivity, which depends on D1 and D2 acting coordinately. These results challenge sequential models of ATP hydrolysis and coupled mechanical work by ClpAP and provide an engineering strategy that will be useful in testing other aspects of ClpAP mechanism.
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