| Achieving correct protein folding and quality control is essential for normal cellular function. The accumulation of misfolded proteins is emerging as central to a wide range of disease states, including many neurodegenerative disorders such as Huntington's and Prion Disease. Molecular chaperones are a diverse family of enzymes that assists the folding of newly translated and stress-denatured proteins, as well as affects protein quality control. The role of chaperones in these diverse functions will be discussed. Biochemical analyses together with systems approaches are used to define the chaperone networks and mechanisms in the eukaryotic cytosol. We find that a chaperone network linked to the protein synthesis apparatus assists protein biogenesis. The emergence of this translation-linked chaperone network likely underlies the elaborate co-translational folding process necessary for the evolution of larger multidomain proteins characteristic of eukaryotic cells. A stress-inducible chaperone network protects cells from environmental stress and assists quality control. These chaperones also communicate with the ubiquitin-proteasome pathway to clear misfolded proteins from the cell. We identify two intracellular compartments for the sequestration of misfolded cytosolic proteins and discuss how our findings provide a framework to understand the link between misfolding and human disease. |
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