![]() ![]() Additionally, the relevance of p23 client maturation, in particular for steroid hormone receptors (SHRs) has been shown in mammalian cells and in yeast expressing SHRs 1, 9, 17, 51, 52. Notably, early studies revealed that a minimal chaperone system of Hsp40, Hsp70, Hsp90, the adaptor protein Hop, and p23 are sufficient to chaperone clients in vitro 46, 47, 49, 50. The binding of p23 to Hsp90 leads to a 50% reduction of the ATPase rate 39, 40, 41, 44 and to prolonged Hsp90 client association 41, 45, 46, 47, 48. However, given that the concentration of p23 in the cell is much lower than that of Hsp90, binding of one p23 per Hsp90 forming an asymmetric complex seems physiologically relevant 35, 42, 43. Interestingly, the stoichiometry of p23 binding is still unclear and both 1:1 and 1:2 (Hsp90 dimer:p23) binding modes have been reported 37, 38, 39, 40, 41. As p23 only binds to the closed conformation of Hsp90, specifically the closed-2 state 35, 36, it is considered as a conformational sensor of the Hsp90 cycle 17, 18. Once both NTDs are in close proximity, the p23 binding site is formed in which p23 is in contact with both Hsp90 monomers 13, 34. Notably, these conformational changes are modulated by a plethora of co-chaperones 30, 31, 32, 33. Importantly, this leads to the reorientation of a catalytic loop in the MD 24. Similar to other chaperones 26, 27, Hsp90 is characterized by high conformational dynamics required for its activity: ATP binding to Hsp90 drives conformational rearrangements of the three domains to change the chaperone from an open/apo state 28 via several intermediates to its closed conformation, in which the two NTDs are intertwined and the NTDs and MDs are twisted 13, 29. Each protomer of the dimeric protein consists of three domains: the N terminal domain (NTD), which harbors the nucleotide-binding site, the middle domain (MD) responsible for completion of the split-ATPase as well as for client binding, and the C terminal domain (CTD), which is required for dimerization and TPR co-chaperone binding 22, 23, 24, 25. Hsp90 is a conserved molecular chaperone involved in the maturation of a diverse client spectrum including disease-related proteins 19, 20, 21. Subsequently, it has been shown that p23 is one of the few co-chaperones that are of general importance for processing diverse client proteins 1, 2. Originally, p23 was discovered as a component of the progesterone receptor complex and was shown to bind to Hsp90 in an ATP-dependent manner 6, 17, 18. The C-terminal extension of p23 is variable in sequence and length it spans 56 amino acids in human p23 and 93 amino acids in yeast p23 and is largely unstructured as shown by CD spectroscopy 15, 16. The folded CHORD and Sgt1 (CS) domains of human and yeast p23 exhibit a highly similar antiparallel β-sandwich structure 12, 13 which corresponds to the fold of the α-crystallin domain of small Hsps 14. P23 consists of two modules, a folded domain and a long unstructured C-terminal tail. At least in part, the positive regulatory effect of p23 on the glucocorticoid receptor (GR) seems to be responsible for this function 8, 11. p23 is not essential in budding and fission yeast, but it is required for perinatal survival in mice 8, 9, 10. An additional, muscle-specific isoform-Aarsd1-has been identified, which replaces p23 during muscle differentiation 7. p23 is a highly conserved protein expressed in eukaryotes ranging from yeast to man 3, 4, 5, 6, while prokaryotes lack orthologues. In contrast to many other co-chaperones it seems to be part of the core chaperone cycle required for efficient client activation 1, 2. The molecular chaperone p23 is an important component of the Hsp90 chaperone machinery. ![]()
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