Quality Control of Protein Folding in the Cytosol

Amie J McClellan, Bennington College, Bennington, Vermont, USA

Published online: May 2012

DOI: 10.1002/9780470015902.a0020886.pub2

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.

Keywords: molecular chaperones; ubiquitin–proteasome system; protein aggregation; protein misfolding; degrons

Figure 1. Pathways of chaperone‐mediated protein folding in the eukaryotic cytosol. Newly synthesised proteins emerge linearly from the ribosome; exposed hydrophobic residues are prevented from off‐pathway folding events by binding to Hsp70. The Hsp70 system is sufficient to fold some proteins (left), whereas other folding substrates require additional folding assistance from TRiC (centre) or Hsp90 (right).
Figure 2. Molecular chaperones modulate misfolded protein conformations and degradation. Chaperones bound to misfolded polypeptides can first attempt refolding to the native state. Failing that, chaperones have the ability to modulate the conformation and subsequent oligomeric state of aggregation‐prone proteins, facilitating the formation of nontoxic, benign conformations that may be subject to clearance by the UPS. In the absence of sufficient chaperone function, soluble toxic intermediates may adversely affect cell viability until ultimately sequestered in inclusion bodies.
Figure 3. Artificial degron sequences projected as helical wheels show hydrophobic faces. The sequences of PB29 (MHSWNFKLYVMGSGAWLL; Sadis et al., 1995) and CL1 (ACKNWFSSLSHFVIHL; Gilon et al., 1998) are shown as helical wheels. Colour key: Yellow=nonpolar/hydrophobic; green=polar, uncharged; blue=basic. Helical wheels created at the following website: http://cti.itc.virginia.edu/∼cmg/Demo/wheel/wheelApp.html
Figure 4. Models for chaperone function in protein triage. A nonnative polypeptide may either fold, aggregate or be targeted for degradation. To facilitate degradation, chaperones may act to prevent aggregation by virtue of repeated cycles of substrate binding and release. Eventually, the misfolded polypeptide is recognised by components of the UPS and committed to degradation (left branch). Alternatively, specific chaperones may interface with E3 ligases, thus actively participating in the targeting and degradation process (right branch).
Figure 5. Schematic of cytosolic quality control pathways in yeast. Ribosome A depicts the synthesis of a soluble misfolded protein that, if it contains a nuclear localisation signal (NLS), will be targeted to the nucleus with the aid of chaperones, ubiquitinated by San1 in the nucleus, and degraded by nuclear proteasomes. If it lacks an NLS, or if its nuclear transport is otherwise compromised, it could instead be ubiquitinated, with the assistance of chaperones, by Ubr1 and degraded by cytosolic proteasomes. Alternatively, chaperones may target the soluble misfolded protein to the ER membrane for ubiquitination by DOA10 and degraded, or the protein may be ubiquitinated by an as yet unidentified E3 ligase and sequestered in a juxtanuclear ER membrane‐bounded compartment (coloured in red). Whether such sequestered proteins are degraded within the compartment or must first exit is not clear at this time. Ribosome B depicts the stalled translational product of a nonstop mRNA, which is ubiquitinated by ribosome‐associated Ltn1 and subsequently degraded. Ribosome C depicts the synthesis of an amyloidogenic protein fated for deposition as an insoluble aggregate in a peripheral perivacuolar compartment (colored in grey). It is unclear whether chaperones participate in delivering such proteins to this compartment, but disaggregase chaperones, such as Hsp104, colocalise with these compartments, as do protein markers for autophagy.
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Related Sub-Topics:

Basic Cell Biology, Protein, RNA and DNA | Protein Folding, Evolution and Degradation | Proteins: Structure, Function, Metabolism
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Article Title: Quality Control of Protein Folding in the Cytosol
 
How to Cite close
McClellan, Amie J(May 2012) Quality Control of Protein Folding in the Cytosol. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020886.pub2]