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Pathways of chaperone-mediated protein folding in the cytosol

Nature Reviews Molecular Cell Biology volume 5, pages 781–791 (2004)Cite this article

Key Points

  • In the cytosol of prokaryotes and eukaryotes, networks of molecular chaperones can assist polypeptides at all stages of folding.

  • The core chaperone machinery — the 70-kDa heat-shock proteins (Hsp70) and chaperonins — is maintained from prokaryotes to eukaryotes, although the chaperone network is expanded in eukaryotes.

  • To help the folding of nascent polypeptides, the chaperone and peptidyl-prolyl isomerase trigger factor, which is docked on the bacterial ribosome, binds them as they emerge from the ribosomal exit site.

  • Eukaryotic Hsp70 chaperones bind nascent chains as they emerge from ribosomes. In Saccharomyces cerevisiae, the ribosome-associated complex recruits the Ssb Hsp70 chaperones to nascent chains.

  • DnaK, which is the Escherichia coli Hsp70, works together with the chaperonin GroEL to fold newly synthesized proteins; polypeptides can be transferred between these chaperones.

  • In eukaryotes, Hsp70 chaperones can cooperate with the chaperonin TCP1 ring complex (TRiC) to fold newly synthesized polypeptides both during and after their translation (for example, some WD40-repeat proteins).

  • The eukaryotic chaperone GimC/prefoldin can bind nascent chains and work with TRiC to fold actin and tubulin.

  • Some eukaryotic polypeptides are passed from the Hsp70 protein HSC70 (70-kDa heat-shock cognate protein) onto chaperones of the Hsp90 (90-kDa heat-shock protein) family, which can work with several co-chaperones to assist the folding of particular proteins.

  • Co-chaperones of HSC70 and HSP90 are also used to sort polypeptides for mitochondrial targeting or to target them for degradation by the proteasome.

Abstract

Cells are faced with the task of folding thousands of different polypeptides into a wide range of conformations. For many proteins, the folding process requires the action of molecular chaperones. In the cytosol of prokaryotic and eukaryotic cells, molecular chaperones of different structural classes form a network of pathways that can handle substrate polypeptides from the point of initial synthesis on ribosomes to the final stages of folding.

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Figure 1: The chaperone network of the prokaryotic cytosol.
Figure 2: The early chaperone network of the eukaryotic cytosol.
Figure 3: The late chaperone network of the eukaryotic cytosol.

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Authors and Affiliations

  1. Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, 3655 Promenade Sir William Osler, Montreal, H3G 1Y6, Quebec, Canada

    Jason C. Young

  2. Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18A, Martinsried, D-82152, Germany

    Vishwas R. Agashe, Katja Siegers & F. Ulrich Hartl

Authors
  1. Jason C. Young
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  2. Vishwas R. Agashe
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  3. Katja Siegers
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  4. F. Ulrich Hartl
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Correspondence to F. Ulrich Hartl.

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DATABASES

Swiss-Prot

AHA1

AIP

BAG1

CDC37

CHIP

ClpB

DJA1

DJB1

DJC7

DnaJ

DnaK

FKB4

GroEL

GroES

GrpE

HOP

HSC70

HSP90

Hsp104

HSPBP1

p23

prefoldin

SGT1

Ssb1

Ssz1

TCP1

TF

TOM70

UNC-45

zuotin

FURTHER INFORMATION

Max-Planck-Institute for Biochemistry: Department for Cellular Biochemistry

Jason Young's web page

Glossary

MOLECULAR CHAPERONES

Proteins that help the folding of other proteins, usually through cycles of binding and release, without forming part of their final native structure.

EXCLUDED VOLUME EFFECT

Extremely high concentrations of inert macromolecules are thought to affect the thermodynamics of reactions between other macromolecules by reducing the available volume in the solution. This effect is observed as an increase in the rates and affinities of intermolecular binding reactions.

TERTIARY STRUCTURE

This term refers to the native three-dimensional conformation of a polypeptide, in which secondary (local) structure elements are packed against each other and specific contacts can form between sections of a polypeptide chain that are widely separated in the amino-acid sequence.

PEPTIDYL-PROLYL CIS–TRANS ISOMERASE

The folding of some proteins requires the rotation of a peptide bond that precedes a proline residue from the trans (extended) to the cis (bent) position, which normally takes place slowly. The peptidyl-prolyl isomerases catalyse this interconversion, which can increase the folding rate of some proteins.

CHAPERONINS

A family of chaperone proteins that have a characteristic double-ring structure. One class of chaperonin, which functions with a capping cofactor, is found in bacteria (for example, GroEL of Escherichia coli), and in the interior of mitochondria and chloroplasts. A second class of chaperonin, which functions without a capping cofactor, is found in the cytosol of eukaryotes (for example, TCP1-ring complex (TRiC)) and in archaea (thermosomes).

IMMUNOPHILINS

A family of intracellular eukaryotic proteins that contain a structurally related peptidyl-prolyl cis–trans isomerase domain and bind immunosuppressive drugs, such as FK506 (rapamycin).

J DOMAIN

A conserved domain that stimulates ATP hydrolysis by chaperones of the 70-kDa heat-shock protein (Hsp70) family. It was first identified in the Escherichia coli co-chaperone DnaJ, but it is also found in DnaJ homologues in eukaryotes, as well as in several co-chaperones that recruit Hsp70 proteins for specific cellular processes.

WD40 REPEAT

A poorly conserved repeat sequence of 40–60 amino acids, which usually ends with Trp-Asp (WD). Several consecutive repeats fold into a circular structure, a so-called β-propeller, in which each blade is a four-stranded β-sheet. This domain is found in proteins that have various different functions.

TETRATRICOPEPTIDE REPEAT-CLAMP DOMAIN

(TPR-clamp domain). TPR motifs are 34-amino-acid degenerate repeat sequences. Some eukaryotic co-chaperones of the cytosolic 70- and 90-kDa heat-shock proteins (HSC70 and HSP90, respectively) contain specialized TPR-clamp domains, which consist of three TPR motifs and 'clamp' a conserved aspartate residue at the carboxyl termini of HSC70 and HSP90.

SARCOMERE

A specialized structure in striated muscle, in which actin filaments contact numerous molecules of myosin, the motor protein that makes up muscle thick filaments. The movement of actin and myosin filaments past each other provides the driving force for muscle contraction.

KINETOCHORES

Specialized regions on chromosomes that are connected to microtubules and motor proteins during cell division in eukaryotes. Kinetochores function in the separation of chromosome pairs.

SKP1–CULLIN–F-BOX UBIQUITIN-LIGASE COMPLEX

A conserved protein complex in eukaryotes that is named on the basis of three of its characteristic components. It transfers ubiquitin onto specific substrate proteins and polyubiquitylated proteins are targeted for proteasomal degradation. It functions in the regulated degradation of proteins and is also essential for cell division.

U-BOX-TYPE E3 UBIQUITIN LIGASE

A class of ubiquitin-ligase domain that can transfer ubiquitin onto substrate proteins. It was first identified in the Ufd2 protein of Saccharomyces cerevisiae, and has since been found in several proteins from both yeast and mammals.

AAA PROTEINS

'ATPases associated with various cellular activities'. A superfamily of structurally related proteins (usually hexameric), a subset of which function to unfold proteins and a related subset of which function as proteases.

CAPACITOR OF MORPHOLOGY

The 90-kDa heat-shock protein (HSP90) has been proposed to buffer cryptic genetic variability by allowing mutated regulatory proteins to function normally. Phenotypes or morphologies that are associated with these mutations are only observed under stress conditions, when HSP90 function is reduced or overloaded, and favourable phenotypes can then be selected in a heritable manner. This mechanism is referred to as genetic capacitance.

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Young, J., Agashe, V., Siegers, K. et al. Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 5, 781–791 (2004). https://doi.org/10.1038/nrm1492

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