An Acetylation Site in the Middle Domain of Hsp90 Regulates Chaperone Function
Open accessAbstract
Heat-shock protein 90 (Hsp90) chaperones a key subset of signaling proteins and is necessary for malignant transformation. Hsp90 is subject to an array of posttranslational modifications that affect its function, including acetylation. Histone deacetylase (HDAC) inhibitors and knockdown of HDAC6 induce Hsp90 acetylation and inhibit its activity. However, direct determination of the functional consequences of Hsp90 acetylation has awaited mapping of specific sites. We now demonstrate that Hsp90 K294 is acetylated. Mutational analysis of K294 shows that its acetylation status is a strong determinant of client protein and cochaperone binding. In yeast, Hsp90 mutants that cannot be acetylated at K294 have reduced viability and chaperone function compared to WT or to mutants that mimic constitutive acetylation. These data suggest that acetylation/deacetylation of K294 plays an important role in regulating the Hsp90 chaperone cycle.
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Acetylation of the K294 residue in human Hsp90 and its corresponding residue K270 in Saccharomyces cerevisiae is important for Hsp90 function.
“Acetylation of the K294 residue in human Hsp90 and its corresponding residue K270 in Saccharomyces cerevisiae is important for Hsp90 function (16, 21).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [16]
Acetylation of K271 in A. fumigatus corresponds to human Hsp90 site K294.
“Acetylation of this site has been previously described in human Hsp90 following TSA treatment (corresponding to human site K294) (16).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [16]
Arginine is known to mimic a deacetylation status.
“In contrast to alanine, arginine is known to mimic a deacetylation status (16, 21, 25).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [16]
Mutation of lysine to alanine is expected to mimic acetylation.
“Mutation of lysine to alanine is expected to mimic acetylation (16, 21, 25).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [16]
Internal acetylation of lysine residues has recently emerged as an important posttranslational modification of Hsp90.
“Internal acetylation of lysine residues has recently emerged as an important posttranslational modification of Hsp90 (13, 16, 21).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [16]
Acetylation mimic of K271 was sufficient to destabilize Hsp90 function in human and yeast.
“Mutation mimicking acetylation of this site, which was sufficient to destabilize Hsp90 function in human and yeast (16, 21), had no major impact in A. fumigatus.”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [16]
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“However, only the silencing of HDAC4 and 6 were shown to regulate the protein expression level of HIF-1a, by altering its post-translational acetylation and its subsequent interaction with the Hsp70/ Hsp90 chaperone machinery [34;35;36].”
BackgroundInfluential
- Authors
- Scroggins, B. T., Robzyk, K., Wang, D., Marcu, M. G., Tsutsumi, S., Beebe, K., Cotter, R. J., Felts, S., Toft, D., Karnitz, L., Rosen, N., & Neckers, L.
- Affiliations
- National Cancer Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Johns Hopkins University (US)
- Mayo Clinic (US)
- Corresponding author
- Neckers, Len
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2007-01
- Volume
- 25
- Issue
- 1
- Pages
- 151-159
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC1839984
- OpenAlex
- W1994637279
- Cited by
- 413
- References
- 42
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 14 · 2023: 12 · 2022: 15 · 2021: 11 · 2020: 23 · 2019: 22 · 2018: 20 · 2017: 13 · 2016: 19 · 2015: 22 · 2014: 29 · 2013: 27 · 2012: 41
- FWCI
- 12.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (Z01SC010074)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- HSP90, protein acetylation, chaperone activity, HDAC6, histone deacetylase inhibitors, post-translational modification, chaperone cycle, yeast viability
- MeSH terms
- Checkpoint Kinase 1, Acetylation, Amino Acid Sequence, Animals, Chlorocebus aethiops, Humans, Lysine, Molecular Sequence Data, Mutation, Protein Binding, Protein Kinases, Saccharomyces cerevisiae, Protein Structure, Tertiary, HSP90 Heat-Shock Proteins, COS Cells, NIH 3T3 Cells, Mutant Proteins, Mice
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