Details
| Original language | English |
|---|---|
| Article number | e30120 |
| Journal | ELIFE |
| Volume | 6 |
| Publication status | Published - 22 Nov 2017 |
Abstract
Ring-forming AAA+ chaperones exert ATP-fueled substrate unfolding by threading through a central pore. This activity is potentially harmful requiring mechanisms for tight repression and substrate-specific activation. The AAA+ chaperone ClpC with the peptidase ClpP forms a bacterial protease essential to virulence and stress resistance. The adaptor MecA activates ClpC by targeting substrates and stimulating ClpC ATPase activity. We show how ClpC is repressed in its ground state by determining ClpC cryo-EM structures with and without MecA. ClpC forms large two-helical assemblies that associate via head-to-head contacts between coiled-coil middle domains (MDs). MecA converts this resting state to an active planar ring structure by binding to MD interaction sites. Loss of ClpC repression in MD mutants causes constitutive activation and severe cellular toxicity. These findings unravel an unexpected regulatory concept executed by coiled-coil MDs to tightly control AAA+ chaperone activity.
ASJC Scopus subject areas
- Neuroscience(all)
- General Neuroscience
- Immunology and Microbiology(all)
- General Immunology and Microbiology
- Biochemistry, Genetics and Molecular Biology(all)
- General Biochemistry,Genetics and Molecular Biology
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In: ELIFE, Vol. 6, e30120, 22.11.2017.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Regulatory coiled-coil domains promote head-to-head assemblies of AAA+ chaperones essential for tunable activity control
AU - Carroni, Marta
AU - Franke, Kamila B.
AU - Maurer, Michael
AU - Jäger, Jasmin
AU - Hantke, Ingo
AU - Gloge, Felix
AU - Linder, Daniela
AU - Gremer, Sebastian
AU - Turgay, Kürşad
AU - Bukau, Bernd
AU - Mogk, Axel
N1 - Funding information: KBF was supported by the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS). This work was funded by grants of the Deutsche Forschungsgemeinschaft (BB617/17-2 and MO 970/4-2) to BB and AM and a fellowship of the Hannover School for Biomolecular Drug Research to IH and the DFG grants Tu106/8-1 and Tu106/6-2 to KT. The Cryo-EM facility at the Science for Life Laboratory Stockholm University (MC) is supported by grants from the Knut and Alice Wallenberg Foundation and the Family Erling Persson Foundation. We thank Stefan Fleischmann for IT support, Christos Savva for microscopy support, Björn Forsberg and Shintaro Aibara for image-processing discussions, Helen Saibil for support in the early stage of the project and Armgard Janczikowski for technical assistance. KBF was supported by the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS). This work was funded by grants of the Deutsche Forschungsgemein-schaft (BB617/17-2 and MO 970/4–2) to BB and AM and a fellowship of the Hannover School for Biomolecular Drug Research to IH and the DFG grants Tu106/8-1 and Tu106/6-2 to KT. The Cryo-EM facility at the Science for Life Laboratory Stockholm University (MC) is supported by grants from the Knut and Alice Wallenberg Foundation and the Family Erling Persson Foundation. We thank Stefan Fleischmann for IT support, Christos Savva for microscopy support, Björn Forsberg and Shintaro Aibara for image-processing discussions, Helen Saibil for support in the early stage of the project and Armgard Janczikowski for technical assistance.
PY - 2017/11/22
Y1 - 2017/11/22
N2 - Ring-forming AAA+ chaperones exert ATP-fueled substrate unfolding by threading through a central pore. This activity is potentially harmful requiring mechanisms for tight repression and substrate-specific activation. The AAA+ chaperone ClpC with the peptidase ClpP forms a bacterial protease essential to virulence and stress resistance. The adaptor MecA activates ClpC by targeting substrates and stimulating ClpC ATPase activity. We show how ClpC is repressed in its ground state by determining ClpC cryo-EM structures with and without MecA. ClpC forms large two-helical assemblies that associate via head-to-head contacts between coiled-coil middle domains (MDs). MecA converts this resting state to an active planar ring structure by binding to MD interaction sites. Loss of ClpC repression in MD mutants causes constitutive activation and severe cellular toxicity. These findings unravel an unexpected regulatory concept executed by coiled-coil MDs to tightly control AAA+ chaperone activity.
AB - Ring-forming AAA+ chaperones exert ATP-fueled substrate unfolding by threading through a central pore. This activity is potentially harmful requiring mechanisms for tight repression and substrate-specific activation. The AAA+ chaperone ClpC with the peptidase ClpP forms a bacterial protease essential to virulence and stress resistance. The adaptor MecA activates ClpC by targeting substrates and stimulating ClpC ATPase activity. We show how ClpC is repressed in its ground state by determining ClpC cryo-EM structures with and without MecA. ClpC forms large two-helical assemblies that associate via head-to-head contacts between coiled-coil middle domains (MDs). MecA converts this resting state to an active planar ring structure by binding to MD interaction sites. Loss of ClpC repression in MD mutants causes constitutive activation and severe cellular toxicity. These findings unravel an unexpected regulatory concept executed by coiled-coil MDs to tightly control AAA+ chaperone activity.
UR - http://www.scopus.com/inward/record.url?scp=85036556992&partnerID=8YFLogxK
U2 - 10.7554/eLife.30120
DO - 10.7554/eLife.30120
M3 - Article
C2 - 29165246
AN - SCOPUS:85036556992
VL - 6
JO - ELIFE
JF - ELIFE
SN - 2050-084X
M1 - e30120
ER -