These different domains are rearranged both in the context of the individual protomers, as well as with respect to the dimer during ATP hydrolysis 34. Hsp90 is comprised of an N terminal nucleotide-binding domain, joined to a middle domain by a charged linker, which is in turn connected to a C terminal domain that is primarily responsible for dimerization 33. The amino acid sequence of Hch1p is ~35% identical to the Aha1p N domain and it shares both the RKxK and NxNNWHW motifs 19, 30.ĪTP hydrolysis by Hsp90 occurs in the context of a cycle involving extensive conformational rearrangements 31, 32. Canonical Aha1p is comprised of two domains joined by a flexible linker and yeast possess a smaller, related co-chaperone called Hch1p that lacks the C terminal domain (Fig. This sequence is located in the first 11 amino acids of Aha1p: a region that is not resolved in the co-crystal structure of the Aha1p N domain in complex with the Hsp90 middle domain 19. Curiously, the most strongly conserved region in Aha-type co-chaperones is in the N terminal domain and is defined by the NxNNWHW motif (Fig. Certainly this is true for the highly conserved RKxK motif which is not required for interaction with Hsp90 but is necessary for robust ATPase stimulation 19. Presumably their functional conservation is linked to the sequences that they share. 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.
AHA AM I NOT HUMAN GRAPHIC ACTIVATOR
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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