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PubMed: 23746257

Title
Molecular chaperone functions in protein folding and proteostasis.
Journal
Annual review of biochemistry
Volume
82
Issue
None
Pages
323-55
Date
2013-01-01
Authors
Bracher A | Hartl FU | Hayer-Hartl M | Hipp MS | Kim YE

Evidence 1bb35e7a70
JSON

Chaperones that function broadly in de novo folding and refolding (i.e., the chaperonins, Hsp70s, and Hsp90s) are ATP regulated and recognize segments of exposed hydropho- bic amino acid residues, which are later buried in the interior of the natively folded protein.

a(CHEBI:ATP) regulates act(p(HGNCGENEFAMILY:Chaperonins)) View Subject | View Object

Appears in Networks:

a(CHEBI:ATP) regulates act(p(FPLX:HSPA)) View Subject | View Object

Appears in Networks:

a(CHEBI:ATP) regulates act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

bp(GO:"'de novo' protein folding") association act(p(HGNCGENEFAMILY:Chaperonins)) View Subject | View Object

Appears in Networks:

bp(GO:"'de novo' protein folding") association act(p(FPLX:HSPA)) View Subject | View Object

Appears in Networks:

bp(GO:"'de novo' protein folding") association act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

bp(GO:"protein refolding") association act(p(HGNCGENEFAMILY:Chaperonins)) View Subject | View Object

Appears in Networks:

bp(GO:"protein refolding") association act(p(FPLX:HSPA)) View Subject | View Object

Appears in Networks:

bp(GO:"protein refolding") association act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

act(p(FPLX:HSP90)) association bp(GO:"'de novo' protein folding") View Subject | View Object

Appears in Networks:

act(p(FPLX:HSP90)) association bp(GO:"protein refolding") View Subject | View Object

Appears in Networks:

act(p(FPLX:HSPA)) association bp(GO:"'de novo' protein folding") View Subject | View Object

Appears in Networks:

act(p(FPLX:HSPA)) association bp(GO:"protein refolding") View Subject | View Object

Appears in Networks:

act(p(HGNCGENEFAMILY:Chaperonins)) association bp(GO:"'de novo' protein folding") View Subject | View Object

Appears in Networks:

act(p(HGNCGENEFAMILY:Chaperonins)) association bp(GO:"protein refolding") View Subject | View Object

Appears in Networks:

Evidence c74432b5d0
JSON

ATP-independent chaperones, such as the small Hsps, may function as additional holdases that buffer aggregation.

a(CHEBI:ATP) causesNoChange act(p(FPLX:HSPB)) View Subject | View Object

Appears in Networks:

act(p(FPLX:HSPB)) decreases a(MESH:"Protein Aggregates") View Subject | View Object

Appears in Networks:

Evidence 6a8f3fd07c
JSON

GroEL and GroES undergo a complex binding-and-release cycle that is allosterically regulated by ATP binding and hydrolysis in the GroEL subunits (Figure 6b) (4, 77, 100, 136).

a(CHEBI:ATP) regulates complex(p(HGNC:HSPD1), p(HGNC:HSPE1)) View Subject | View Object

Appears in Networks:

Evidence db40077ea1
JSON

The antihypertensive drug guanabenz demonstrates this; besides be- ing an α2 receptor antagonist, it also stabilizes the translation initiation factor 2 (eIF2) in its inactive, phosphorylated state (226).

a(CHEBI:Guanabenz) decreases act(p(FPLX:ADRA2)) View Subject | View Object

Appears in Networks:

a(CHEBI:Guanabenz) decreases act(p(FPLX:EIF2B)) View Subject | View Object

Appears in Networks:

a(CHEBI:Guanabenz) increases p(FPLX:EIF2B, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(FPLX:EIF2B, pmod(Ph)) decreases act(p(FPLX:EIF2B)) View Subject | View Object

Appears in Networks:

Evidence 4a60c7fd02
JSON

For exam- ple, small molecules (e.g., geldanamycin) that activate heat shock factor 1, the main transcrip- tional regulator of the cytosolic stress response, increase the effective concentration of cytosolic chaperones and suppress the aggregation of various disease proteins (8, 38, 228–230).

a(CHEBI:geldanamycin) increases act(p(HGNC:HSF1)) View Subject | View Object

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p(HGNC:HSF1) regulates bp(GO:"cellular response to stress") View Subject | View Object

Appears in Networks:

p(HGNC:HSF1) increases a(MESH:"Molecular Chaperones") View Subject | View Object

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p(HGNC:HSF1) decreases a(MESH:"Protein Aggregates") View Subject | View Object

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Evidence c624848828
JSON

A key role of molecular chaperones is preventing pro- tein aggregation, especially under conditions of cellular stress.

a(MESH:"Molecular Chaperones") decreases a(MESH:"Protein Aggregates") View Subject | View Object

Appears in Networks:

Evidence a206fed0a1
JSON

Hsp70 chaperones are a ubiquitous class of proteins. They are involved in a wide range of protein quality control functions, including de novo protein folding, refolding of stress- denatured proteins, protein transport, mem- brane translocation, and protein degradation.

bp(GO:"'de novo' protein folding") association act(p(FPLX:HSPA)) View Subject | View Object

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bp(GO:"intracellular protein transmembrane transport") association act(p(FPLX:HSPA)) View Subject | View Object

Appears in Networks:

bp(GO:"protein catabolic process") association act(p(FPLX:HSPA)) View Subject | View Object

Appears in Networks:

bp(GO:"protein refolding") association act(p(FPLX:HSPA)) View Subject | View Object

Appears in Networks:

act(p(FPLX:HSPA)) association bp(GO:"'de novo' protein folding") View Subject | View Object

Appears in Networks:

act(p(FPLX:HSPA)) association bp(GO:"protein refolding") View Subject | View Object

Appears in Networks:

act(p(FPLX:HSPA)) association bp(GO:"intracellular protein transmembrane transport") View Subject | View Object

Appears in Networks:

act(p(FPLX:HSPA)) association bp(GO:"protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence 200f15475b
JSON

After hydrolysis the Hsp90 N termini separate, releasing the client protein in an active state (Figure 7b).

bp(GO:"ATP metabolic process") increases act(p(FPLX:HSP90)) View Subject | View Object

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act(p(FPLX:HSP90)) increases bp(GO:"protein folding") View Subject | View Object

Appears in Networks:

Evidence 26808f34fe
JSON

Additionally, PN regulation is integrated with pathways involved in inflam- mation, response to oxidative stress, caloric restriction/starvation, and longevity.

bp(GO:"behavioral response to starvation") association bp(HBP:Proteostasis) View Subject | View Object

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bp(GO:"cell death") negativeCorrelation bp(HBP:Proteostasis) View Subject | View Object

Appears in Networks:

bp(GO:"inflammatory response") association bp(HBP:Proteostasis) View Subject | View Object

Appears in Networks:

bp(GO:"response to oxidative stress") association bp(HBP:Proteostasis) View Subject | View Object

Appears in Networks:

bp(HBP:Proteostasis) association bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:

bp(HBP:Proteostasis) association bp(GO:"response to oxidative stress") View Subject | View Object

Appears in Networks:

bp(HBP:Proteostasis) association bp(GO:"behavioral response to starvation") View Subject | View Object

Appears in Networks:

bp(HBP:Proteostasis) negativeCorrelation bp(GO:"cell death") View Subject | View Object

Appears in Networks:

Evidence ac4b591981
JSON

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82).

bp(GO:"calcium-mediated signaling") association p(FPLX:HSP90) View Subject | View Object

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bp(GO:"cell cycle") association p(FPLX:HSP90) View Subject | View Object

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bp(GO:"immune response") association p(FPLX:HSP90) View Subject | View Object

Appears in Networks:

bp(GO:"protein secretion") association p(FPLX:HSP90) View Subject | View Object

Appears in Networks:

bp(GO:"protein transport") association p(FPLX:HSP90) View Subject | View Object

Appears in Networks:

bp(GO:"steroid hormone mediated signaling pathway") association p(FPLX:HSP90) View Subject | View Object

Appears in Networks:

bp(MESH:"Heat-Shock Response") association p(FPLX:HSP90) View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) association bp(GO:"cell cycle") View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) association bp(GO:"steroid hormone mediated signaling pathway") View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) association bp(GO:"calcium-mediated signaling") View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) association bp(GO:"protein transport") View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) association bp(GO:"protein secretion") View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) association bp(GO:"immune response") View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) association bp(MESH:"Heat-Shock Response") View Subject | View Object

Appears in Networks:

Evidence 893b48ef63
JSON

Many are stress proteins or heat shock proteins (Hsps), as their synthesis is induced under conditions of stress (e.g., heat shock or oxidative stress), which structurally destabilize a subset of cellular proteins.

bp(GO:"response to oxidative stress") increases a(MESH:"Heat-Shock Proteins") View Subject | View Object

Appears in Networks:

bp(MESH:"Heat-Shock Response") increases a(MESH:"Heat-Shock Proteins") View Subject | View Object

Appears in Networks:

bp(MESH:"Stress, Physiological") increases a(MESH:"Heat-Shock Proteins") View Subject | View Object

Appears in Networks:

Evidence 3fd30acd2d
JSON

The PN is regulated by interconnected pathways that respond to specific forms of cellular stress, including the cytosolic heat shock response (HSR) (191), the unfolded protein response (UPR) in the endoplas- mic reticulum (192), and the mitochondrial UPR (193).

bp(GO:"response to unfolded protein") regulates bp(HBP:Proteostasis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endoplasmic Reticulum
MeSH
Mitochondria

bp(MESH:"Heat-Shock Response") regulates bp(HBP:Proteostasis) View Subject | View Object

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Annotations
MeSH
Cytosol

Evidence 7f43cfd327
JSON

Indeed, studies using model organisms demonstrate that a gradual decline in cellular proteostasis capacity occurs with aging (10).

bp(GO:aging) decreases bp(HBP:Proteostasis) View Subject | View Object

Appears in Networks:

Evidence ae847cfb90
JSON

As shown in Caenorhabditis elegans, Drosophila, and the mouse, the ability of cells and tissues to maintain proteostasis declines during aging, concurrent with the capacity to respond to conformational stresses (214–220).

bp(GO:aging) decreases bp(HBP:Proteostasis) View Subject | View Object

Appears in Networks:

Evidence 862d9ca458
JSON

The PN branch of degradation includes the ubiquitin- proteasome system (UPS) and machinery of autophagy (23, 196–200).

bp(GO:autophagy) increases bp(GO:"protein catabolic process") View Subject | View Object

Appears in Networks:

p(FPLX:Proteasome) increases bp(GO:"protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence 3f28c1a867
JSON

Aggregated proteins that cannot be un- folded for proteasomal degradation may be removed by autophagy and lysosomal/vacuolar degradation.

bp(GO:autophagy) decreases a(MESH:"Protein Aggregates") View Subject | View Object

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Evidence 51f75b7723
JSON

Inhibition of ATP binding and hydrolysis either by mutagenesis of the N domain or by specific inhibitors, such as geldanamycin and radicicol, demonstrated the functional requirement of the Hsp90 ATPase (81, 169).

complex(a(CHEBI:ATP), p(FPLX:HSP90)) regulates act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

Evidence d3166b206d
JSON

Cooperative binding of ATP to GroEL initiates a series of conformational changes that trigger the association of GroES, followed by substrate release from hydrophobic binding sites into a GroES-capped, hydrophilic folding chamber (137).

complex(a(CHEBI:ATP), p(HGNC:HSPD1)) increases complex(p(HGNC:HSPD1), p(HGNC:HSPE1)) View Subject | View Object

Appears in Networks:

Evidence 6cc68b18b3
JSON

Binding to GroEL prevents aggregation of these flexible folding intermediates, and subsequent folding depends critically on the global encapsulation of the substrate in the chaperonin cavity by the cochaperone GroES (7, 132–135).

p(HGNC:HSPD1) decreases a(MESH:"Protein Aggregates") View Subject | View Object

Appears in Networks:

complex(p(HGNC:HSPD1), p(HGNC:HSPE1)) increases bp(GO:"protein refolding") View Subject | View Object

Appears in Networks:

Evidence 4a5d60526f
JSON

TRiC binds to nascent chains and cooperates with Hsp70 in the cotranslational folding of multidomain proteins (78). Investigators have demonstrated a direct interaction between Hsp70 and TRiC (79).

complex(p(FPLX:"CCT_complex"), p(FPLX:HSPA)) increases bp(GO:"'de novo' protein folding") View Subject | View Object

Appears in Networks:

Evidence 87170decb3
JSON

TRiC also interacts with N-terminal fragments of mutant huntingtin that contain an expanded polyglutamine repeat sequence (165–168). Binding to TRiC modulates the aggregation properties of this protein and reduces its cytotoxicity.

p(FPLX:"CCT_complex") decreases a(HBP:"huntingtin aggregates") View Subject | View Object

Appears in Networks:

Evidence ecdb1e1592
JSON

This approach is based on multiple lines of evidence demonstrating that overexpression of chaperones such as Hsp70 and Hsp40 prevents the aggregation and toxicity of huntingtin and α-synuclein (38, 231–234).

p(FPLX:HSPA) decreases a(HBP:"huntingtin aggregates") View Subject | View Object

Appears in Networks:

p(FPLX:HSPA) decreases a(HBP:"alpha-synuclein aggregates") View Subject | View Object

Appears in Networks:

p(HGNCGENEFAMILY:"DNAJ (HSP40) heat shock proteins") decreases a(HBP:"huntingtin aggregates") View Subject | View Object

Appears in Networks:

p(HGNCGENEFAMILY:"DNAJ (HSP40) heat shock proteins") decreases a(HBP:"alpha-synuclein aggregates") View Subject | View Object

Appears in Networks:

Evidence af591a9e4c
JSON

The Hsp70 system acts synergistically with the cytosolic chaperonin TRiC to prevent aggregation of proteins with expanded polyglutamine tracts (165–168).

composite(p(FPLX:"CCT_complex"), p(FPLX:HSPA)) decreases a(MESH:"Protein Aggregates") View Subject | View Object

Appears in Networks:

composite(p(FPLX:"CCT_complex"), p(FPLX:HSPA)) decreases a(HBP:"huntingtin aggregates") View Subject | View Object

Appears in Networks:

Evidence 9ab4261d81
JSON

For example, Hsp70 and Hsp90 cooperate with the U-box-dependent ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein) and a variety of other cofactors (such as BAG1 and BAG3) to ubiquitinate client proteins (23, 86, 198).

composite(p(FPLX:HSP90), p(FPLX:HSPA), p(HGNC:BAG1), p(HGNC:BAG3), p(HGNC:STUB1)) increases bp(GO:"protein ubiquitination") View Subject | View Object

Appears in Networks:

Evidence 6d7baa1d3e
JSON

BAG1 targets proteins for degradation by the UPS, whereas BAG3 mediates degradation by macroautophagy.

p(HGNC:BAG1) increases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

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p(HGNC:BAG3) increases bp(GO:macroautophagy) View Subject | View Object

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Evidence 97785850c7
JSON

Hsp110 may function as holdases for nonnative proteins and cooperate with Hsp70 and Hsp40 in protein disaggregation (104, 124, 125).

composite(p(FPLX:HSPA), p(HGNC:HSPH1), p(HGNCGENEFAMILY:"DNAJ (HSP40) heat shock proteins")) decreases a(MESH:"Protein Aggregates") View Subject | View Object

Appears in Networks:

Evidence dfced8419b
JSON

Hsp40 ( J protein) and NEF cochaperones regulate the Hsp70 reaction cy- cle (38, 100).

p(HGNCGENEFAMILY:"DNAJ (HSP40) heat shock proteins") regulates act(p(FPLX:HSPA)) View Subject | View Object

Appears in Networks:

p(FPLX:RAPGEF) regulates act(p(FPLX:HSPA)) View Subject | View Object

Appears in Networks:

Evidence 30fe4753e5
JSON

Degradation via the UPS depends on pro- tein unfolding by the 26S proteasome (201) and generally requires that chaperones maintain target proteins in a nonaggregated state.

p(FPLX:Proteasome) increases bp(GO:"protein unfolding") View Subject | View Object

Appears in Networks:

Evidence be2ab3b828
JSON

The activator of Hsp90 ATPase (Aha1) binds asymmetrically to the Hsp90 middle domain, stimulating ATP hydrolysis and inducing transition to the closed state (180, 181, 185, 190).

p(HGNC:AHSA1) increases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

Appears in Networks:

Evidence 17248cbba3
JSON

Cochaperones HOP (Sti1) and Cdc37 (p50) stabilize the open conformation of the Hsp90 dimer (81, 174, 175, 188), inhibit ATP hydrolysis, and facilitate substrate protein binding.

p(HGNC:CDC37) decreases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

Appears in Networks:

p(HGNC:STIP1) decreases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

Appears in Networks:

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