Aha1 can act as an autonomous chaperone to prevent aggregation of stressed proteins.
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.
From the Department of Cardiovascular Physiology, Ruhr-University Bochum, 44801 Bochum, Germany.
Vishwadeepak
V
Tripathi
From the Department of Cardiovascular Physiology, Ruhr-University Bochum, 44801 Bochum, Germany.
Stefanie
S
Darnauer
From the Department of Cardiovascular Physiology, Ruhr-University Bochum, 44801 Bochum, Germany.
Nadine R
NR
Hartwig
From the Department of Cardiovascular Physiology, Ruhr-University Bochum, 44801 Bochum, Germany Wolfgang.Obermann@rub.de.
Wolfgang M J
WM
Obermann
D000818:Animals; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D049409:Luciferases, Firefly / Q000737:chemistry; D008253:Macaca mulatta; D051379:Mice; D018832:Molecular Chaperones / Q000737:chemistry / Q000502:physiology*; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011485:Protein Binding; D058849:Protein Refolding; D059748:Proteolysis; D013884:Thiosulfate Sulfurtransferase / Q000737:chemistry; D054875:Ubiquitination
C515652:AHSA1 protein, human; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D049409:Luciferases, Firefly; D013884:Thiosulfate Sulfurtransferase
ATPase; Activator of Hsp90 ATPase (Aha1); Heat Shock Protein 90 (Hsp90); Molecular Chaperone; Protein Aggregation; Protein Folding