Abstract
Aha1 (activator of Hsp90 ATPase) stimulates the ATPase activity of the molecular chaperone Hsp90 to accelerate the conformational cycle during which client proteins attain their final shape. Thereby, Aha1 promotes effective folding of Hsp90-dependent clients such as steroid receptors and many kinases involved in cellular signaling. In our current study, we find that Aha1 plays a novel, additional role beyond regulating the Hsp90 ATP hydrolysis rate. We propose a new concept suggesting that Aha1 acts as an autonomous chaperone and associates with stress-denatured proteins to prevent them from aggregation similar to the chaperonin GroEL. Our study reveals that an N-terminal sequence of 22 amino acids, present in human but absent from yeast Aha1, is critical for this capability. However, in lieu of fostering their refolding, Aha1 allows ubiquitination of bound clients by the E3 ubiquitin ligase CHIP. Accordingly, Aha1 may promote disposal of folding defective proteins by the cellular protein quality control.
Highlights
Molecular chaperones assist proteins to gain their three-dimensional conformation or triage damaged proteins for degradation
We find that Aha1 plays a novel, additional role beyond regulating the heat shock protein 90 (Hsp90) ATP hydrolysis rate
We consistently find the majority of Aha1 independent of Hsp90 as a self-contained protein suggesting that Aha1 may serve additional functions beyond the stimulation of Hsp90 ATPase activity
Summary
Molecular chaperones assist proteins to gain their three-dimensional conformation or triage damaged proteins for degradation. Thereby, Aha promotes effective folding of Hsp90-dependent clients such as steroid receptors and many kinases involved in cellular signaling. A couple of cochaperone proteins such as Sti1/Hop, Cdc37/p50, Sba1/p23, and Aha regulate the ATPase activity of the molecular chaperone and may thereby adjust the speed of the Hsp conformational cycle to the demands of a particular client protein [4, 13]. The association between Hsp and the cochaperones Aha and Cdc37/p50 that regulate its ATP hydrolysis rate is controlled by phosphorylation of the molecular chaperone at distinct tyrosine residues during the chaperone cycle [17]. Rather than attempting to refold bound clients, Aha holds them for ubiquitination by the cellular protein quality control.
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