PubMed: 23746257

Molecular chaperone functions in protein folding and proteostasis.
Annual review of biochemistry
Bracher A | Hartl FU | Hayer-Hartl M | Hipp MS | Kim YE

Evidence 1bb35e7a70

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.

Evidence c74432b5d0

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

Evidence 6a8f3fd07c

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).

Evidence db40077ea1

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).

Evidence 4a60c7fd02

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).

Evidence c624848828

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

Evidence a206fed0a1

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.

Evidence 200f15475b

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

Evidence 26808f34fe

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

Evidence ac4b591981

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).

Evidence 893b48ef63

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.

Evidence 3fd30acd2d

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).

Evidence 7f43cfd327

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

Evidence ae847cfb90

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).

Evidence 862d9ca458

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

Evidence 3f28c1a867

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

Evidence 51f75b7723

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).

Evidence d3166b206d

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).

Evidence 6cc68b18b3

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).

Evidence 4a5d60526f

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).

Evidence 87170decb3

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.

Evidence ecdb1e1592

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).

Evidence af591a9e4c

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

Evidence 9ab4261d81

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).

Evidence 6d7baa1d3e

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

Evidence 97785850c7

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

Evidence dfced8419b

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

Evidence 30fe4753e5

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.

Evidence be2ab3b828

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).

Evidence 17248cbba3

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.


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