Mutant analysis reveals allosteric regulation of ClpB disaggregase
The members of the hexameric AAA+ disaggregase of E. coli and S. cerevisiae, ClpB and Hsp104, cooperate with the Hsp70 chaperone system in the solubilization of aggregated proteins. Aggregate solubilization relies on a substrate threading activity of ClpB/Hsp104 fueled by ATP hydrolysis in both ATPa...
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| Hauptverfasser: | , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
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22 February 2017
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Frontiers in molecular biosciences
Year: 2017, Jahrgang: 4 |
| ISSN: | 2296-889X |
| DOI: | 10.3389/fmolb.2017.00006 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.3389/fmolb.2017.00006 Verlag, kostenfrei, Volltext: https://www.frontiersin.org/articles/10.3389/fmolb.2017.00006/full 
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| Verfasserangaben: | Kamila B. Franke, Bernd Bukau and Axel Mogk (Center for Molecular Biology of the Heidelberg University, German Cancer Research Center, Heidelberg, Germany) |
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| 245 | 1 | 0 | |a Mutant analysis reveals allosteric regulation of ClpB disaggregase |c Kamila B. Franke, Bernd Bukau and Axel Mogk (Center for Molecular Biology of the Heidelberg University, German Cancer Research Center, Heidelberg, Germany) |
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| 520 | |a The members of the hexameric AAA+ disaggregase of E. coli and S. cerevisiae, ClpB and Hsp104, cooperate with the Hsp70 chaperone system in the solubilization of aggregated proteins. Aggregate solubilization relies on a substrate threading activity of ClpB/Hsp104 fueled by ATP hydrolysis in both ATPase rings (AAA-1, AAA-2). ClpB/Hsp104 ATPase activity is controlled by the M-domains, which associate to the AAA-1 ring to downregulate ATP hydrolysis. Keeping M-domains displaced from the AAA-1 ring by association with Hsp70 increases ATPase activity due to enhanced communication between protomers. This communication involves conserved arginine fingers. The control of ClpB/Hsp104 activity is crucial, as hyperactive mutants with permanently dissociated M-domains exhibit cellular toxicity. Here, we analyzed AAA-1 inter-ring communication in relation to the M-domain mediated ATPase regulation, by subjecting a conserved residue of the AAA1 domain subunit interface of ClpB (A328) to mutational analysis. While all A328X mutants have reduced disaggregation activities, their ATPase activities strongly differed. ClpB-A328I/L mutants have reduced ATPase activity and, when combined with the hyperactive ClpB-K476C M-domain mutation, suppress cellular toxicity. This underlines that ClpB ATPase activation by M-domain dissociation relies on increased subunit communication. The ClpB-A328V mutant in contrast has very high ATPase activity and exhibits cellular toxicity on its own, qualifying it as novel hyperactive ClpB mutant. ClpB-A328V hyperactivity is, however, different from that of M-domain mutants as M-domains stay associated with the AAA-1 ring. The high ATPase activity of ClpB-A328V primarily relies on the AAA-2 ring and correlates with distinct conformational changes in the AAA-2 catalytic site. These findings characterize the subunit interface residue A328 as crucial regulatory element to control ATP hydrolysis in both AAA rings. | ||
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