From hatching to dispatching: the multiple cellular roles of the Hsp70 molecular chaperone machinery
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Figure 1
Hsc70 and its cochaperones function in both protein folding and degradation. (A) Schematic of the Hsc70 ATPase cycle. For Hsc70 mediated folding cycles of client protein binding and release are coupled to conformational change of the chaperone, driven by ATP hydrolysis and exchange. (1) Hsp40 (shown as a dimer in the schematic) captures nascent or misfolded client proteins and presents them to Hsc70. Other DnaJ proteins can substitute for Hsp40. (2) J-domain stimulates the ATPase activity of Hsc70 resulting in conformational change and ‘clamping’ of client protein in the substrate-binding pocket. (3) Hip stabilizes the client protein bound ADP state of Hsc70 further promoting folding. (4) Bag protein binding stimulates nucleotide exchange. In humans HspBP1 and Hsp110 can also act as Hsc70 nucleotide exchange factors. (5) Client proteins may undergo multiple cycles of Hsc70 binding and release before reaching a natively folded state. (6) ATP-bound Hsc70 is in the ‘open’ conformation. (B) Hsc70 cochaperone complexes that promote client protein ubiquitination and proteasomal degradation are illustrated. CHIP interacts with Hsc70 via a TPR domain and acts as an ubiquitin ligase for Hsc70 clients, recruiting ubiquitin conjugating enzyme (Ubc) family members through its U-box domain. HSJ1 binds ubiquitin chains on Hsc70 clients via its ubiquitin interaction motifs, protecting them from chain trimming by ubiquitin hydrolases. HSJ1 also presents client to Hsc70 and is also able to stimulate ATPase activity via its J-domain. Bag-1 binds to Hsc70 via its Bag domain and interacts directly with the proteasome via an ubiquitin-like domain (Arndt et al. 2007).
- © 2009 Society for Endocrinology
