![]() ![]() The Aha-type co-chaperones are among the more weakly conserved proteins with the yeast Aha1p and human Ahsa1 sharing only 23% identity but they stimulate the ATPase activity of Hsp90 in a similar manner 30. ![]() ![]() Co-chaperone proteins are not nearly as well conserved at the level of primary sequence but many are functionally interchangeable between yeast and humans 27, 28, 29. Hsp90 is highly conserved with yeast and human Hsp90 possessing ~60% identity. The cellular activity of Hsp90 appears to be influenced by the relative expression levels of Aha1 and other co-chaperones which are normally far less abundant than the chaperone itself 25, 26. ![]() Modulating Aha1 levels, and presumably the Hsp90 ATPase activity, has been shown to alter the folding of the cystic transmembrane conductance regulator (CFTR) and its export from the ER 20, kinase activation 21, 22, 23, and the activity of other clients 21, 22, 24. The activator of Hsp90 ATPase, Aha1, is the most potent stimulator of the Hsp90 ATPase activity identified to date 18, 19. The importance of the Hsp90 ATPase activity has drawn a great deal of attention to the co-chaperones that regulate it. How the Hsp90 functional cycle is regulated in the context of client maturation is poorly understood but it is clear that ATP hydrolysis is critical for efficient client maturation by Hsp90 16, 17. Co-chaperones regulate conformational transitions in Hsp90, ATP binding and hydrolysis, as well as client interaction 14, 15. Client activation during the Hsp90 functional cycle is regulated by a cohort of proteins called co-chaperones 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. The 90 kDa heat shock protein (Hsp90) is a dimeric molecular chaperone that promotes the folding and maturation of a large but specific group of substrates called client proteins 1, 2. ![]()
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