Quality Control of Protein Folding in the Cytosol

Abstract

In order to function properly, newly synthesised proteins must rapidly and efficiently attain their native conformations. If they fail to do so, the cell may be adversely affected due to loss of function or toxic gain of function effects of misfolded polypeptides. Effective quality control mechanisms to recognise and eliminate misfolded proteins are thus critical for cell viability. The primary means by which misfolded proteins are selectively removed from the cell is via the ubiquitin–proteasome system. Although much is known about regulated proteolysis, how any given protein, which could potentially misfold, is recognised and targeted for proteasome-mediated degradation has been challenging to decipher. Recent progress, much of it in yeast, has identified specific E3 ligases involved in this process, clarified or added to our knowledge of the roles of molecular chaperones, and identified multiple cellular locations where degradation, or failing that, aggregation, occurs.

Key Concepts:

• Molecular chaperones facilitate the folding of newly synthesised proteins to their native states and thus are critical for the maintenance of cellular proteome integrity.

• Cellular proteostasis reflects the balance between protein folding and degradation.

• Proteins that fail to fold properly must be eliminated via cellular quality control systems to avoid potentially damaging effects on the cell.

• The ubiquitin–proteasome system is the primary means for the selective removal of misfolded proteins.

• Molecular chaperones can tip the balance between protein folding and degradation, and facilitate the destruction of misfolded proteins.

• E3 ligases have been identified that either cooperate with chaperones, or that directly interact with nonnative proteins to target them for degradation.

• The degradation of misfolded cytosolic proteins in eukaryotes occurs in multiple cellular locations.