Abstract
A protein quality control system, consisting of molecular chaperones and proteases, controls the folding status of proteins and prevents the aggregation of misfolded proteins by either refolding or degrading aggregation-prone species. During severe stress conditions this protection system can be overwhelmed by high substrate load, resulting in the formation of protein aggregates. In such emergency situations, Hsp104/ClpB becomes a key player for cell survival, as it has the extraordinary capacity to rescue proteins from an aggregated state in cooperation with an Hsp70 chaperone system. The ring-forming Hsp104/ClpB chaperone belongs to the AAA+ protein superfamily, which in general drives the assembly and disassembly of protein complexes by ATP-dependent remodelling of protein substrates. A disaggregation activity was also recently attributed to other eubacterial AAA+ proteins, while such an activity has not yet been identified in mammalian cells. In this review, we report on new insights into the mechanism of protein disaggregation by AAA+ proteins, suggesting that these chaperones act as molecular crowbars or ratchets.
Highlights
To cope with these stresses a group of highly conserved proteins has evolved, specialized in assisting the folding of nascent polypeptides and the refolding of misfolded proteins
Even more striking was the finding that large electron-dense aggregates that formed after heat shock in the nucleus and the cytoplasm of S. cerevisiae were the main target of Hsp104 action [7]
The unique function of Hsp104 is conserved in eubacteria, plants and mitochondria by its homologues ClpB, Hsp101 and Hsp78, which each are essential for thermotolerance and protein disaggregation [8,9,10,11,12,13]
Summary
SFtirguucrteur2al features of AAA+ proteins Structural features of AAA+ proteins. (A) Domain organization and cooperating proteins of AAA+ chaperones. These residues appear to be located on mobile loops, as the corresponding regions could not be resolved in the ClpB crystal structure [24] These observations suggest that Hsp104/ClpB may, like peptidase-associated AAA+ proteins, exhibit a translocation activity that could mediate the extraction of an unfolded polypeptide from the aggregate (Fig. 3). ClpC, like ClpP, localizes to protein aggregates in heat-shocked B. subtilis cells and to inclusion bodies formed by overexpressed insoluble heterologous proteins [58,59] These data suggest that ClpC might replace ClpB function in the gram-positive counterpart of E. coli, it rather links protein disaggregation to substrate degradation instead of substrate reactivation. It is tempting to speculate that solubilization of inclusion bodies relies on the disaggregation activity of AAA+ proteins (e.g. ClpB/ DnaK) Together these findings offer a new perspective to increase the solubility of a wide variety of heterologous proteins upon overproduction in eubacteria
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