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PreprintCited by 7Heat shock proteins researchBacterial Genetics and BiotechnologyEnzyme Structure and Function

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Structure of the central Staphylococcus aureus AAA+ protease MecA/ClpC/ClpP

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Azinas, Stavros, Wallden, Karin, Katikaridis, Panagiotis, Jenne, Timo, Schahl, Adrien, Mogk, Axel, Carroni, Marta·2025·Communications Biology
DOI 10.1101/2025.06.06.658286PMC PMC12521514

Preprint — published as 10.1038/s42003-025-08908-w · Paper page

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Abstract

Bacterial AAA+ proteases are composed of a AAA+ partner (e.g. ClpC) and an associated peptidase (e.g. ClpP). They represent ATP-fuelled and self-compartmentalized proteolytic machines that are crucial for stress resistance and virulence. ClpC requires cooperation with adaptor proteins such as MecA for activation and complex formation with ClpP. Here, we present the cryo-EM structure of the MecA/ClpC/ClpP complex from the major pathogen Staphylococcus aureus . MecA forms a dynamic crown on top of the ClpC/ClpP complex with its substrate-binding domain positioned near the ClpC pore site, likely facilitating substrate transfer. ClpC/ClpP complex formation involves ClpC P-loops and ClpP N-terminal β-hairpins, which insert into the central ClpC threading channel and contact sites next to the ClpC ATPase center. ClpC and ClpP interactions are asymmetric and dictated by the activity states of ClpC ATPase subunits. ClpP binding increases ClpC ATPase and threading activities in a β-hairpin dependent manner, illuminating an allosteric pathway in the cooperation of ATPase and peptidase components in bacterial AAA+ proteases.

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Metadata

Authors
Azinas, S., Wallden, K., Katikaridis, P., Jenne, T., Schahl, A., Mogk, A., & Carroni, M.
Affiliations
  • Stockholm University (SE)
  • German Cancer Research Center (DE)
Corresponding author
  • Mogk, Axel
  • Carroni, Marta
ORCID
Venue
Communications Biology
Publisher
openRxiv
Published
2025-06-06
Volume
8
Issue
1
Pages
1467-1467
ISSN
2399-3642 (ISSN-L)
DOI
10.1101/2025.06.06.658286
PMC
PMC12521514
OpenAlex
W4415157247
Cited by
7
References
1
Citations by year
2026: 7
FWCI
2.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Deutsche Forschungsgemeinschaft (MO 970/8-1, 970/8-1)
  • Knut och Alice Wallenbergs Stiftelse (KAW 2021.0347, KAW 2021)
  • Stockholms Universitet
  • Science for Life Laboratory
  • Stiftelsen för Strategisk Forskning
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
AAA+ protease, mecA gene, ClpC, ClpP, Staphylococcus aureus, substrate-binding domain, ATPase activity, allosteric regulation, beta-hairpin, P-loop, substrate transfer, stress tolerance, virulence
MeSH terms
Bacterial Proteins, Heat-Shock Proteins, Models, Molecular, Protein Binding, Protein Conformation, Staphylococcus aureus, Cryoelectron Microscopy, Penicillin-Binding Proteins, Endopeptidase Clp

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