Molecular chaperones antagonize proteotoxicity by differentially modulating protein aggregation pathways

Abstract

The self-association of misfolded or damaged proteins into ordered amyloid-like aggregates characterizes numerous neurodegenerative disorders. Insoluble amyloid plaques are diagnostic of many disease states. Yet soluble, oligomeric intermediates in the aggregation pathway appear to represent the toxic culprit. Molecular chaperones regulate the fate of misfolded proteins and thereby influence their aggregation state. Chaperones conventionally antagonize aggregation of misfolded, disease proteins and assist in refolding or degradation pathways. Recent work suggests that chaperones may also suppress neurotoxicity by converting toxic, soluble oligomers into benign aggregates. Chaperones can therefore suppress or promote aggregation of disease proteins to ameliorate the proteotoxic accumulation of soluble, assembly intermediates.

Figure 1

Schematic representation of the amyloid assembly pathway. A disease causing protein can adopt a non-native conformation due to intrinsic and/or environmental stress. The misfolded, disease protein can then self-associate into different intermediate structures such as detergent-soluble oligomers and/or protofibrils whose intracellular accumulation correlate with cell death. In this model, we speculate about the structural properties of the ill-defined intermediates. Alternatively, the misfolded protein can accumulate as non-specific, amorphous aggregates. The formation of amyloid seeds drives the autocatalytic conversion of native and misfolded protein monomers into β-sheet-rich, amyloid aggregates.

Figure 2

Hsp70-Hsp40 hydrolytic cycle for the binding and refolding of non-native proteins. A native protein can adopt a non-native conformation. Hsp40 co-chaperones can recognize the misfolded protein and bind it via its polypeptide binding domain. Hsp40 delivers the non-native substrate to Hsp70 and its J-domain stimulated ATP hydrolysis on Hsp70. This promotes a conformational change in Hsp70 via closure of the lid domain and increases the binding affinity of Hsp70 for the substrate. Hsp70 along with other cellular components not shown in this model can assist in the proper refolding of the substrate. Nucleotide exchange factors (NEF) release ADP and load ATP back onto the nucleotide binding domain of Hsp70 which promotes substrate release.

Figure 3

Roles for Sis1 in [RNQ⁺] prion assembly. The [RNQ⁺] prion acts as a template to alter the conformation of native Rnq1 into an assembly competent monomer. Sis1 promotes the appropriate packaging of templated Rnq1 monomers into higher-ordered [RNQ⁺] prions via a fragmentation and elongation model. Inefficiencies in this assembly process by Rnq1 overexpression or Sis1 depletion enable templated monomers to accumulate as soluble, proteotoxic species.