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.
ATP-independent chaperones, such as the small Hsps, may function as additional holdases that buffer aggregation.
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).
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).
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 key role of molecular chaperones is preventing pro- tein aggregation, especially under conditions of cellular stress.
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.
After hydrolysis the Hsp90 N termini separate, releasing the client protein in an active state (Figure 7b).
Additionally, PN regulation is integrated with pathways involved in inflam- mation, response to oxidative stress, caloric restriction/starvation, and longevity.
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).
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.
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).
Indeed, studies using model organisms demonstrate that a gradual decline in cellular proteostasis capacity occurs with aging (10).
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).
The PN branch of degradation includes the ubiquitin- proteasome system (UPS) and machinery of autophagy (23, 196–200).
Aggregated proteins that cannot be un- folded for proteasomal degradation may be removed by autophagy and lysosomal/vacuolar degradation.
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).
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).
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).
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).
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.
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).
The Hsp70 system acts synergistically with the cytosolic chaperonin TRiC to prevent aggregation of proteins with expanded polyglutamine tracts (165–168).
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).
BAG1 targets proteins for degradation by the UPS, whereas BAG3 mediates degradation by macroautophagy.
Hsp110 may function as holdases for nonnative proteins and cooperate with Hsp70 and Hsp40 in protein disaggregation (104, 124, 125).
Hsp40 ( J protein) and NEF cochaperones regulate the Hsp70 reaction cy- cle (38, 100).
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.
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).
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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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.