The Mechanism of Hsp90 ATPase Stimulation by Aha1
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Hsp90 is a dimeric molecular chaperone responsible for the folding, maturation, and activation of hundreds of substrate proteins called 'clients'. Numerous co-chaperone proteins regulate progression through the ATP-dependent client activation cycle. The most potent stimulator of the Hsp90 ATPase activity is the co-chaperone Aha1p. Only one molecule of Aha1p is required to fully stimulate the Hsp90 dimer despite the existence of two, presumably identical, binding sites for this regulator. Using ATPase assays with Hsp90 heterodimers, we find that Aha1p stimulates ATPase activity by a three-step mechanism via the catalytic loop in the middle domain of Hsp90. Binding of the Aha1p N domain to the Hsp90 middle domain exerts a small stimulatory effect but also drives a separate conformational rearrangement in the Hsp90 N domains. This second event drives a rearrangement in the N domain of the opposite subunit and is required for the stimulatory action of the Aha1p C domain. Furthermore, the second event can be blocked by a mutation in one subunit of the Hsp90 dimer but not the other. This work provides a foundation for understanding how post-translational modifications regulate co-chaperone engagement with the Hsp90 dimer.
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The difference in in vitro ATPase IC50 is not sufficient alone to explain the cellular-level observation because in vivo Hsp90 ATPase activity is regulated by cochaperones.
“However, since in vivo ATPase activity of Hsp90 is known to be regulated by many cochaperones which either stimulate or bring down Hsp90 ATPase activity, the difference in ATPase IC50 observed in vitro is not sufficient alone to explain the observation at the cellular level.”
From Heat shock protein 90 localizes to the surface and augments virulence factors of Cryptococcus neoformans (2017) · cites this paper as [31]
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Li, W., & Liu, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.845585 · Cited by 24 · see citing works
Dual Roles for Yeast Sti1/Hop in Regulating the Hsp90 Chaperone Cycle
Reidy, M., Kumar, S., Anderson, D. E., & Masison, D. C. (2018) · Genetics · doi:10.1534/genetics.118.301178 · Cited by 22 · see citing works
Cochaperones convey the energy of ATP hydrolysis for directional action of Hsp90
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Evidence for Hsp90 Co-chaperones in Regulating Hsp90 Function and Promoting Client Protein Folding
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Detecting Posttranslational Modifications of Hsp90
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Heat Shock Proteins and Endoplasmic Reticulum Stress
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Wilkie, A. O. M. (2017) · Nature Genetics · doi:10.1038/ng.3776 · Cited by 13 · see citing works
Wolmarans, A., Kwantes, A., & LaPointe, P. (2018) · Biological Chemistry · doi:10.1515/hsz-2018-0251 · Cited by 13 · see citing works
Self-citationSmall molecules targeting molecular chaperones for tau regulation: Achievements and challenges
He, C., Gu, J., Wang, D., Wang, K., Wang, Y., You, Q., & Wang, L. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115859 · Cited by 12 · see citing works
The evolution and diversification of the Hsp90 co-chaperone system
Engler, S., & Büchner, J. (2025) · Biological Chemistry · doi:10.1515/hsz-2025-0112 · Cited by 12 · see citing works
Reidy, M. J., & Masison, D. C. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2020.06.015 · Cited by 12 · see citing works
Molecular mechanism of bacterial Hsp90 pH‐dependent ATPase activity
Jin, Y., Hoxie, R. S., & Street, T. O. (2017) · Protein Science · doi:10.1002/pro.3174 · Cited by 12 · see citing works
Sumi, M. P., Tupta, B., Roychowdhury, S., COMHAIR, S. A. A., Asosingh, K., Stuehr, D. J., ERZURUM, S. C., & Ghosh, A. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102717 · Cited by 11 · see citing works
Mercier, R., Yama, D., LaPointe, P., & Johnson, J. L. (2023) · PLoS Genetics · doi:10.1371/journal.pgen.1010772 · Cited by 11 · see citing works
Aha-type co-chaperones: the alpha or the omega of the Hsp90 ATPase cycle?
LaPointe, P., Mercier, R., & Wolmarans, A. (2019) · Biological Chemistry · doi:10.1515/hsz-2019-0341 · Cited by 11 · see citing works
Self-citationMolecular chaperones: Guardians of tumor suppressor stability and function
Heritz, J. A., Backe, S. J., & Mollapour, M. (2024) · Oncotarget · doi:10.18632/oncotarget.28653 · Cited by 10 · see citing works
The Adaptive Potential of the Middle Domain of Yeast Hsp90
Cote-Hammarlof, P. A., Fragata, I., Flynn, J. M., Mavor, D., Zeldovich, K. B., Bank, C., & Bolon, D. N. A. (2020) · Molecular Biology and Evolution · doi:10.1093/molbev/msaa211 · Cited by 10 · see citing works
p23 and Aha1: Distinct Functions Promote Client Maturation
Biebl, M. M., & Büchner, J. (2022) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-3-031-14740-1_6 · Cited by 9 · see citing works
Maintenance of protein homeostasis in glia extends lifespan in C. elegans
Wang, L., & Bianchi, L. K. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113648 · Cited by 8 · see citing works
AHA1 regulates cell migration and invasion via the EMT pathway in colorectal adenocarcinomas
Kim, D., Moon, J. W., Min, D. H., Ko, E. S., Ahn, B., Kim, E. S., & Lee, J.-Y. (2021) · Scientific Reports · doi:10.1038/s41598-021-99375-w · Cited by 9 · see citing works
DNA damage-induced nuclear import of HSP90α is promoted by Aha1
Fangaria, N., Rani, K., Singh, P., Dey, S., Kumar, K. A., & Bhattacharyya, S. (2022) · Molecular Biology of the Cell · doi:10.1091/mbc.e21-11-0554 · Cited by 9 · see citing works
Astl, L., Stetz, G., & Verkhivker, G. M. (2020) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c00380 · Cited by 8 · see citing works
AHSA1 Regulates Hepatocellular Carcinoma Progression via the TGF-β/Akt-Cyclin D1/CDK6 Pathway
Gao, Y., Li, Y., Liu, Z., Dong, Y., Yang, S., Wu, B., Xiao, M., Chen, C., Wen, Y., Chen, L., et al. (2023) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s407680 · Cited by 7 · see citing works
Chowdhury, S. R., Koley, T., Singh, M., Ethayathulla, A. S., & Kaur, P. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188883 · Cited by 6 · see citing works
Amoah, D. P., Hussein, S. K., Johnson, J. L., & LaPointe, P. (2024) · Protein Science · doi:10.1002/pro.5255 · Cited by 6 · see citing works
The GHKL ATPase Family as a Paradigm for MutL Homolog Function in DNA Mismatch Repair
Piscitelli, J. M., & Manhart, C. M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262412157 · Cited by 5 · see citing works
Saccharomyces cerevisiae as a tool for deciphering Hsp90 molecular chaperone function
Backe, S. J., Mollapour, M., & Woodford, M. R. (2023) · Essays in Biochemistry · doi:10.1042/ebc20220224 · Cited by 5 · see citing works
Asymmetric Dynamics Drive Catalytic Activation of the Hsp90 Chaperone
Magnan, B., Chen, X., Rashid, S., Minard, A., Chau, W., Uyesugi, T., Edwards, R. A., Panigrahi, R. R., Glover, J. N. M., LaPointe, P., et al. (2024) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.4c03363 · Cited by 5 · see citing works
Progress in Molecular Chaperone Regulation of Heat Shock Protein 90 and Cancer
Rui, Z., Xiao-Yun, G., Xing-Chuang, X., Jiang, Y., Huang, Z., & Xiang, F. (2018) · Chinese Journal of Analytical Chemistry · doi:10.1016/s1872-2040(17)61071-5 · Cited by 4 · see citing works
The role of Aha1 in cancer and neurodegeneration
Blagg, B. S. J., & Catalfano, K. C. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1509280 · Cited by 3 · see citing works
Gene expression and functional analysis of Aha1a and Aha1b in stress response in zebrafish
Xiao, H., Wang, H., He, Q., Zhou, J., & Du, S. (2022) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2022.110777 · Cited by 3 · see citing works
Potential use of heat shock protein 90 as a biomarker for the diagnosis of human diseases
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Detecting Posttranslational Modifications of Hsp90 Isoforms
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Collaboration between two conserved sequence motifs drives ATPase stimulation of Hsp90 by Aha1
Amoah, D. P., Mercier, R., Alyousef, G., Johnson, J. L., & LaPointe, P. (2025) · Protein Science · doi:10.1002/pro.70359 · Cited by 1 · see citing works
Singh, S., Saini, V., Shevtsov, M., & Jha, H. C. (2025) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2025.11.005 · Cited by 1 · see citing works
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FRET Assays for the Identification of C. albicans HSP90-Sba1 and Human HSP90α-p23 Binding Inhibitors
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Role of Hsp90 Interacting Molecular Chaperones on Tau and Aß Processing in Alzheimer’s Disease
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The adaptive potential of the middle domain of yeast Hsp90Preprint
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Prognostic values and clinical relationship of AHSA1 in hepatocellular carcinomaPreprint
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AHA1 regulates Aβ production via modulation of APP expression and γ-secretase assemblyPreprint
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AHA1 Regulates Aβ Production via Modulation of APP Abundance and γ‐Secretase Assembly
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Dores-Silva, P. R., Seraphim, T. V., Minari, K., da Silva, I. R. F., Gomes, W. P. C., de Sousa, L. F., da Rocha, A. M. F., Barbosa, L. R. S., Joseph, J. S., & Borges, J. C. (2026) · FEBS Journal · doi:10.1111/febs.70776
- Authors
- Wolmarans, A., Lee, B., Spyracopoulos, L., & LaPointe, P.
- Affiliations
- University of Alberta (CA)
- Corresponding author
- LaPointe, Paul
- Venue
- Scientific Reports
- Published
- 2016-09-12
- Volume
- 6
- Issue
- 1
- Pages
- 33179-33179
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5018835
- OpenAlex
- W2519427278
- Cited by
- 72
- References
- 72
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 6 · 2023: 9 · 2022: 10 · 2021: 5 · 2020: 8 · 2019: 6 · 2018: 8 · 2017: 7
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Alberta Innovates
- Canadian Institutes of Health Research (97870, 110964)
- Natural Sciences and Engineering Research Council of Canada (386803)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- HSP90, Aha1, ATPase activity, co-chaperones, molecular chaperones, catalytic loop, conformational change, N-domain, post-translational modification
- MeSH terms
- Adenosine Triphosphatases, Adenosine Triphosphate, Enzyme Activation, Escherichia coli, Kinetics, Protein Binding, Saccharomyces cerevisiae, Chaperonins, HSP90 Heat-Shock Proteins, Catalytic Domain, Amino Acid Motifs, Saccharomyces cerevisiae Proteins
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