Aha1 competes with Hop, p50 and p23 for binding to the molecular chaperone Hsp90 and contributes to kinase and hormone receptor activation.
The ATP-dependent molecular chaperone Hsp90 (heat-shock protein 90) is essential for the maturation of hormone receptors and protein kinases. During the process of client protein activation, Hsp90 co-operates with cofactors/co-chaperones of unique sequence, e.g. Aha1 (activator of Hsp90 ATPase 1), p23 or p50, and with cofactors containing TPR (tetratricopeptide repeat) domains, e.g. Hop, immunophilins or cyclophilins. Although the binding sites for these different types of cofactors are distributed along the three domains of Hsp90, sterical overlap and competition for binding sites restrict the combinations of cofactors that can bind to Hsp90 at the same time. The recently discovered cofactor Aha1 associates with the middle domain of Hsp90, but its relationship to other cofactors of the molecular chaperone is poorly understood. Therefore we analysed whether complexes of Aha1, p23, p50, Hop and a cyclophilin with Hsp90 are disrupted by the other four cofactors by gel permeation chromatography using purified proteins. It turned out that Aha1 competes with the early cofactors Hop and p50, but can bind to Hsp90 in the presence of cyclophilins, suggesting that Aha1 acts as a late cofactor of Hsp90. In contrast with p50, which can bind to Hop, Aha1 does not interact directly with any of the other four cofactors. In vivo studies in yeast and in mammalian cells revealed that Aha1 is not specific for kinase activation, but also contributes to maturation of hormone receptors, proposing a general role for this cofactor in the activation of Hsp90-dependent client proteins.
Harst
Anja
A
Protein Folding Group, Institute for Genetics, University of Bonn, Römerstr. 164, D-53117 Bonn, Germany.
Lin
Hongying
H
Obermann
Wolfgang M J
WM
D001667:Binding, Competitive / Q000502:physiology*; D002460:Cell Line; D018833:Chaperonins; D004789:Enzyme Activation; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry*; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*
C475092:AHA1 protein, S cerevisiae; D018841:HSP90 Heat-Shock Proteins; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D029701:Saccharomyces cerevisiae Proteins; D018833:Chaperonins