![]() It is found as a dimer, with each monomer composed of three domains (Supplementary Fig. Hsp90 is also a very abundant, well-conserved chaperone. After this process, the Hsp70:substrate binds cochaperone Bag1, which carries a Bag domain that interacts with Hsp70 and a Ubl domain that links the complex to the proteasome 19. Once the Hsp70:substrate complex is formed, it must interact with CHIP for substrate ubiquitination. Several studies have shown that in stressful conditions, CHIP overexpression correlates directly with proteasomal degradation of substrates such as cystic fibrosis transmembrane conductance regulator (CFTR) 11, glucocorticoid receptor (GR) 12, the E2A transcription factor 13, tau 14, huntingtin and ataxin 15, telomerase 16, apoptosis signal-regulating kinase 1 (ASK1) 17, phosphatase and tensin homologue (PTEN) 18 and p53 6. The two domains are connected by a very flexible, well-conserved linker.ĬHIP-mediated degradation in Hsp70 has been characterised in detail 10. 1b) its substrate-binding domain (Hsp70 SBD 25 kDa) recognizes the client protein and acts like forceps to trap it, and the nucleotide-binding domain (Hsp70 NBD 45 kDa) controls opening and closing of the Hsp70 SBD. It is a small, two-domain ATPase (70 kDa) (Supplementary Fig. Hsp70 is a universally conserved chaperone with important functions in protein folding and disaggregation 9, but whose pivotal role in protein degradation is only now beginning to be understood. Although it acts as a homodimer, CHIP has an unusual asymmetric structure with a triangular, concave shape in which one U-box domain is blocked, which might have biological consequences 7. It is the latter which connects to an E2 ubiquitin-conjugating enzyme, which in turn ubiquitinates Hsp70- and Hsp90-bound client proteins and targets them to the proteasome for degradation 8. 1a): the TPR domain which interacts with chaperones Hsp70 and Hsp90 a coiled-coil domain involved in CHIP dimerization and a U-box domain. CHIP has three domains 7 (Supplementary Fig. The cochaperone C terminus of Hsc70-interacting protein (CHIP) is the best-characterised member of this type of E3 ligases 5, 6. Chaperone-assisted UPS involves interaction of the chaperone-bound substrate with a cochaperone, which acts as an E3 ligase and assists substrate ubiquitination prior to its delivery to the proteasome 4. ![]() The fate of the chaperone-bound client protein is dictated by interactions with cochaperones, which drive the substrate towards folding or degradation.ĭegradation operates via one of the two general protein degradation pathways: the ubiquitin–proteasome system (UPS), or autophagy. ![]() Molecular chaperones are central to proteostasis, as they are involved not only in protein folding but also in degradation 2, 3. Interruption of this process contributes to a variety of pathologies including neurodegenerative disorders and cancer 1. Protein homeostasis, or proteostasis, is the delicate balance of synthesis, folding, trafficking, and degradation of intra- and extracellular proteins. These complexes are inherently flexible, which is important for the ubiquitination process. The 3D structures of the two complexes, obtained using a combination of cryoelectron microscopy and crosslinking mass spectrometry, showed the substrate located between the chaperone and the cochaperone, suggesting a ubiquitination mechanism in which the chaperone-bound substrate is presented to CHIP. Both ternary complexes (Hsp70:p53-TMGST:CHIP and Hsp90:p53-TMGST:CHIP) ubiquitinated the substrate at a higher efficiency than in the absence of the chaperones. We generated complexes between the chaperones (Hsp70 or Hsp90), the cochaperone CHIP and, as substrate, a p53 variant containing the GST protein (p53-TMGST). This is the case for Hsp70 and Hsp90 which, in concert with the cochaperone CHIP, direct their bound substrate to degradation through ubiquitination. Some molecular chaperones are involved not only in assisting the folding of proteins but also, given appropriate conditions, in their degradation.
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