Protein rescue from aggregates by powerful molecular chaperone machines

Abstract

Protein quality control within the cell requires the interplay of many molecular chaperones and proteases. When this quality control system is disrupted, polypeptides follow pathways leading to misfolding, inactivity and aggregation. Among the repertoire of molecular chaperones are remarkable proteins that forcibly untangle protein aggregates, called disaggregases. Structural and biochemical studies have led to new insights into how these proteins collaborate with co-chaperones and utilize ATP to power protein disaggregation. Understanding how energy-dependent protein disaggregating machines function is universally important and clinically relevant, as protein aggregation is linked to medical conditions such as Alzheimer's disease, Parkinson's disease, amyloidosis and prion diseases.

Single-molecule Analyses of the Dynamics of Heat Shock Protein 104 (Hsp104) and Protein Aggregates

“…As described above, extensive efforts over the past decade have elucidated the basic mechanism of Hsp104/ClpB as a molecular machine (1,2). However, the process by which Hsp104-Hsp70 solubilizes the substrate aggregates remains poorly understood.…”

“…Misfolded or aggregated proteins damaged by cellular stresses such as heat shock, trigger impaired cellular protein homeostasis and proteostasis, eventually leading to serious disorders in cells (1,2). To protect against these threats, molecular chaperones promote protein folding and prevent the accumulation of aggregated proteins in the cell (1,2).…”

“…To protect against these threats, molecular chaperones promote protein folding and prevent the accumulation of aggregated proteins in the cell (1,2). In the yeast Saccharomyces cerevisiae, Hsp104 is essential for thermotolerance (3,4).…”

“…In the yeast Saccharomyces cerevisiae, Hsp104 is essential for thermotolerance (3,4). Hsp104, a member of the ATPases associated with diverse cellular activities (AAAϩ) superfamily, has homologs in fungi and prokaryotes, including Escherichia coli ClpB (1,2,5).…”

Specific Chaperones and Regulatory Domains in Control of Amyloid Formation

“…Because soluble and aggregated yeast prions represent transcription factors in their active and inactive states, respectively, their distribution during cell division results in non-genetic inheritance (48). Prion assembly is regulated by parts of the proteostasis network responsible for protein folding and quality control in general (49). Its chief component is heat shock protein (Hsp)104, an ATP-driven disaggregase with the unique ability to dissociate amyloid fibrils (50).…”