Chaperone-assisted protein aggregate reactivation: Different solutions for the same problem

Aguado, Alejandra; Fernández-Higuero, José Ángel; Moro, Fernando; Muga, Arturo

doi:10.1016/j.abb.2015.07.006

Cited by 28 publications

(20 citation statements)

References 197 publications

(393 reference statements)

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“…ClpB chaperone has been shown, in various organisms, to be involved in the disaggregation of protein aggregates formed as a result of stress [48]. Intracellularly, ClpB is present in two forms, a WT and an N-terminally truncated form lacking the NTD due to an internal translation start site.…”

Section: Discussionmentioning

confidence: 99%

The amino‐terminal domain of Mycobacterium tuberculosis ClpB protein plays a crucial role in its substrate disaggregation activity

et al. 2018

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Mycobacterium tuberculosis ( Mtb ) is known to persist in extremely hostile environments within host macrophages. The ability to withstand such proteotoxic stress comes from its highly conserved molecular chaperone machinery. ClpB, a unique member of the AAA + family of chaperones, is responsible for resolving aggregates in Mtb and many other bacterial pathogens. Mtb produces two isoforms of ClpB, a full length and an N‐terminally truncated form (ClpB∆N), with the latter arising from an internal translation initiation site. It is not clear why this internal start site is conserved and what role the N‐terminal domain ( NTD ) of Mtb ClpB plays in its function. In the current study, we functionally characterized and compared the two isoforms of Mtb ClpB. We found the NTD to be dispensable for oligomerization, ATP ase activity and prevention of aggregation activity of ClpB. Both ClpB and ClpB∆N were found to be capable of resolubilizing protein aggregates. However, the efficiency of ClpB∆N at resolubilizing higher order aggregates was significantly lower than that of ClpB. Further, ClpB∆N exhibited reduced affinity for substrates as compared to ClpB. We also demonstrated that the surface of the NTD of Mtb ClpB has a hydrophobic groove that contains four hydrophobic residues: L97, L101, F140 and V141. These residues act as initial contacts for the substrate and are crucial for stable interaction between ClpB and highly aggregated substrates.

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Section: Discussionmentioning

confidence: 99%

The amino‐terminal domain of Mycobacterium tuberculosis ClpB protein plays a crucial role in its substrate disaggregation activity

et al. 2018

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“…That metazoans do not have an obvious homolog of the potent AAA+ Hsp104/ClpB disaggregase found in prokaryotes and fungi has been a conundrum [36]. A recent report indicates that metazoans have evolved a different way to deal with disassembly and refolding of aggregated proteins, dependent on physical interaction between two different types of double β-barrel domain J-proteins (Box 3) [37].…”

Section: Chaperone Contacts That Make the System Workmentioning

confidence: 99%

How Do J-Proteins Get Hsp70 to Do So Many Different Things?

Craig

Marszałek

2017

Trends in Biochemical Sciences

173

184

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Hsp70 chaperone machineries play pivotal roles in a wide array of fundamental biological processes, through their facilitation of protein folding, disaggregation and remodeling. Hsp70’s obligate J-protein co-chaperones drive much of this remarkable multi-functionality, with most Hsp70s having multiple J-protein partners. Recent data suggest that J-protein-driven versatility is substantially due to precise localization within the cell and specificity of substrate protein binding. However, this relatively simple view belies the intricacy of J-protein function. Examples are emerging of J-protein interactions with Hsp70 and other chaperones, as well as integration into broader cellular networks. These interactions fine-tune, in critical ways, the ability of Hsp70 to participate in diverse cellular processes.

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“…However, during severe stress the capacity of this protective system becomes exhausted due to appearance of excess amounts of misfolded proteins and their aggregation. Once physiological conditions are restored, the aggregation process is reversed by specialized chaperones, disaggregases, capable of reactivation of proteins trapped in aggregates ( Aguado et al, 2015 ; Doyle et al, 2013 ; Kim et al, 2013 ; Mogk et al, 2015 ). In yeast Saccharomyces cerevisiae this role is played by the Hsp104 chaperone, essential for development of tolerance to stress ( Sanchez and Lindquist, 1990 ) and for propagation of prions ( Chernoff et al, 1995 ).…”

Section: Introductionmentioning

confidence: 99%

Adenosine diphosphate restricts the protein remodeling activity of the Hsp104 chaperone to Hsp70 assisted disaggregation

Kłosowska

Chamera

Liberek

2016

eLife

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Hsp104 disaggregase provides thermotolerance in yeast by recovering proteins from aggregates in cooperation with the Hsp70 chaperone. Protein disaggregation involves polypeptide extraction from aggregates and its translocation through the central channel of the Hsp104 hexamer. This process relies on adenosine triphosphate (ATP) hydrolysis. Considering that Hsp104 is characterized by low affinity towards ATP and is strongly inhibited by adenosine diphosphate (ADP), we asked how Hsp104 functions at the physiological levels of adenine nucleotides. We demonstrate that physiological levels of ADP highly limit Hsp104 activity. This inhibition, however, is moderated by the Hsp70 chaperone, which allows efficient disaggregation by supporting Hsp104 binding to aggregates but not to non-aggregated, disordered protein substrates. Our results point to an additional level of Hsp104 regulation by Hsp70, which restricts the potentially toxic protein unfolding activity of Hsp104 to the disaggregation process, providing the yeast protein-recovery system with substrate specificity and efficiency in ATP consumption.DOI: http://dx.doi.org/10.7554/eLife.15159.001

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Chaperone-assisted protein aggregate reactivation: Different solutions for the same problem

Cited by 28 publications

References 197 publications

The amino‐terminal domain of Mycobacterium tuberculosis ClpB protein plays a crucial role in its substrate disaggregation activity

The amino‐terminal domain of Mycobacterium tuberculosis ClpB protein plays a crucial role in its substrate disaggregation activity

How Do J-Proteins Get Hsp70 to Do So Many Different Things?

Adenosine diphosphate restricts the protein remodeling activity of the Hsp104 chaperone to Hsp70 assisted disaggregation

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