Chaperones, Chaperonins and Heat‐Shock Proteins

Abstract

The protein folding of a nascent polypeptide is the decoding of the linear information contained in the primary sequence into the native and functionally active three‐dimensional conformation. Chaperone proteins and folding catalysts may contribute to successful folding into the native and active protein conformation in the crowded cellular environment, thus avoiding aggregation of non‐native protein forms. Molecular chaperones in vivo play a pivotal role in the maintenance of the proteome quality control and in the correct balance between protein folding and degradation. The unbalance of the equilibrium between protein synthesis, protein folding and protein degradation may contribute to protein misfolding and aggregation which may lead to the onset of several degenerative diseases associated with protein aggregation, such as Alzheimer's and Huntington's disease.

Key Concepts

  • The native protein conformation is the active and functional form of the protein in vivo.
  • Protein chaperones assist several proteins in the folding to their native conformation.
  • Protein chaperones contribute to maintain the correct balance between protein synthesis and degradation.
  • Chaperones are ubiquitous proteins and are present in all the cells and in all the cellular compartments.
  • Most of chaperones require adenosine triphosphate for their function.
  • Chaperones prevent protein misfolding and aggregation that may be associated to several degenerative diseases.

Keywords: protein folding; chaperones; folding catalysts; proteostasis

Figure 1. The oxidative formation of protein disulfides catalysed by PDI. The protein may be involved in the formation of disulfide bonds (a) or in their rearrangement (b).
Figure 2. Modular organisation of the domains in protein disulfide isomerase‐related proteins. (A) Crystal structure of reduced (PDB ID: 4EKZ) and (B) oxidised (PDB ID: 4EL1) human PDI. The four thioredoxin‐like domains are arranged in a horseshoe shape: the two redox‐active domains (a, a′) are located at the opening of the horseshoe and are separated by the two thioredoxin‐related domains (b, b′). (C) Schematic representation of the modular organisation of PDI.
Figure 3. Isomerisation of peptide bonds. (a) The steric hindrance around the amide bond favours the trans‐conformation of a peptide bond. (b) cis–trans isomerisation of a peptidyl–prolyl bond.
Figure 4. Basic mechanism of E. coli GroEL‐GroES‐assisted folding. The vertical section of GroEL double ring shows the apical (orange), intermediate (green) and equatorial (blue) domains.
Figure 5. Basic mechanism of Hsp70‐assisted folding. ADP‐bound, closed state (PDB ID: 3HSC and 1DKZ); ATP‐bound, open state (PDB ID: 4B9Q). Nucleotide‐binding domain, substrate‐binding domain and α‐helical lid are represented in deep blue, cyan and pink, respectively. NEF, nucleotide exchange factor.
Figure 6. Basic mechanism of Hsp90‐assisted folding. The dimeric Hsp90 undergoes conformational changes induced by ATP binding and hydrolysis. Open state (PDB ID: 2IOQ), partly closed state. ADP‐bound (PDB ID: 2OIV), closed state. ATP‐bound (PDB ID: 2CG9), N‐terminal domain, middle domain and C‐terminal domain are represented in deep blue, green and pink, respectively.
Figure 7. Trigger factor and general organisation of molecular chaperones in the cytosol. (a) Domain organisation and three‐dimensional structure of E. coli Trigger factor (TF, PDB ID: 1W26): the N‐terminal domain (N, green) contains the ribosome‐binding region and is connected by a long loop to the peptidyl‐prolyl cis–trans isomerase domain (PPI, purple), the C‐terminal domain (C, red) contains the binding site for the nascent polypeptide chain and occupies the central part of the protein. (b) The ribosome‐binding chaperones (TF in Bacteria or NAC in Eukarya) interact directly with the ribosome and assist co‐translational folding. Co‐ and post‐translational folding of the nascent polypeptide chain may also require the mediation of other chaperones: Hsp70s in Eukarya and DnaK in Bacteria.
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people.cryst.bbk.ac.uk/∼ubcg16z/chaperone.html

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Consalvi, Valerio, and Chiaraluce, Roberta(Jun 2015) Chaperones, Chaperonins and Heat‐Shock Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000641.pub3]