Chaperoning proteins for destruction: diverse roles of Hsp70 chaperones and their co-chaperones in targeting misfolded proteins to the proteasome - PubMed (original) (raw)
Review
Chaperoning proteins for destruction: diverse roles of Hsp70 chaperones and their co-chaperones in targeting misfolded proteins to the proteasome
Ayala Shiber et al. Biomolecules. 2014.
Abstract
Molecular chaperones were originally discovered as heat shock-induced proteins that facilitate proper folding of proteins with non-native conformations. While the function of chaperones in protein folding has been well documented over the last four decades, more recent studies have shown that chaperones are also necessary for the clearance of terminally misfolded proteins by the Ub-proteasome system. In this capacity, chaperones protect misfolded degradation substrates from spontaneous aggregation, facilitate their recognition by the Ub ligation machinery and finally shuttle the ubiquitylated substrates to the proteasome. The physiological importance of these functions is manifested by inefficient proteasomal degradation and the accumulation of protein aggregates during ageing or in certain neurodegenerative diseases, when chaperone levels decline. In this review, we focus on the diverse roles of stress-induced chaperones in targeting misfolded proteins to the proteasome and the consequences of their compromised activity. We further discuss the implications of these findings to the identification of new therapeutic targets for the treatment of amyloid diseases.
Figures
Figure 1
Misfolded protein quality control: making the correct triage decision. Preferentially, the misfolded protein is refolded, keeping the active protein pool constant. However, if the protein cannot refold to its native conformation, it can be removed by Ub-dependent proteasomal degradation. If the chaperone and/or the degradation machineries become rate limiting, misfolded proteins are likely to aggregate. Both degradation and aggregation reduce the active pool of the protein. The proteasome cartoon was adapted from Nickell et al. [3].
Figure 2
The Hsp70 machinery functions in multiple steps during Ub-mediated proteasomal degradation. (a) Prior to ubiquitylation: (I) Heat shock protein (HSP) activity maintains the solubility of misfolded proteins by shielding exposed hydrophobic features; (II) HSP binding targets the substrate to the ubiquitylation complex; (b) Following ubiquitylation: (III) HSPs assist delivery of the ubiquitylated substrate to the proteasome; (IV) HSPs may additionally protect ubiquitylated substrates from Ub-mediated sequestration.
Figure 3
The Hsp70 machinery reaction cycle. (I) Hsp40 mediates the delivery of nascent or misfolded proteins to ATP-bound Hsp70; (II) Hydrolysis of ATP to ADP, accelerated by the Hsp40, results in Hsp70 conformational change: the α Helical “lid” of the peptide binding domain “closes”, leading to tight binding of the substrate. Hsp40 dissociates from Hsp70; (III) NEF (Nucleotide exchange factor) binds to Hsp70, catalyzing the dissociation of ADP (IV); (V) ATP binds to the Hsp70’s ATPase domain, inducing “opening” of the “lid”, thereby enabling substrate release.
Figure 4
Different nucleotide exchange factors direct the HSP machinery toward refolding or degradation of misfolded substrates. In yeast, most of the cytosolic Hsp70 clients, targeted for degradation are ubiquitylated by the E3 ligases San1/Ubr1. Hsp110 promotes rebinding of misfolded substrates to the Hsp70 machinery, thus assisting protein folding. Conversely, Fes1 stimulates misfolded protein release from the Hsp70 machinery, promoting binding to the E3 ligase. In metazoans, BAG-1 mediates proteasomal degradation by recruiting the Hsp70/CHIP/substrate complex to the proteasome while BAG-2 inhibits CHIP activity, thus promoting refolding.
Figure 5
Hsp40/70 requirement is determined by the severity of protein misfolding. Terminally as well as partially misfolded proteins require Hsp40 activity for initial sorting of the ubiquitylation complex. However, only terminally misfolded proteins require the Hsp70s prior to ubiquitylation. The HSP70s may be needed for maintaining misfolded substrate solubility and/or for assisting interaction with the ubiquitylation complex. Still, both terminally and partially misfolded ubiquitylated substrates require Hsp70s activity for 26S proteasome degradation.
Figure 6
The cellular consequences of misfolded protein aggregation upon Hsp70 depletion. Hsp70s depletion, as happens during ageing, induces spontaneous aggregation of terminally misfolded proteins, enhancing sequestration of molecular chaperones and additional critical factors, and thereby their cytosolic depletion. On the other hand, partially misfolded proteins remain soluble, until they are tagged for degradation by Ub conjugation. However, when Hsp70 levels are limiting, the ubiquitylated substrates are not degraded by the 26S proteasome. Instead, they undergo Ub-mediated sequestration, which may require the association with proteins containing Ub binding domain (UBDs).
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