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Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition
Open accessAbstract
HSP90 is a molecular chaperone that associates with numerous substrate proteins called clients. It plays many important roles in human biology and medicine, but determinants of client recognition by HSP90 have remained frustratingly elusive. We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37. Unexpectedly, many more kinases than transcription factors bound HSP90. CDC37 interacted with kinases, but not with transcription factors or E3 ligases. HSP90::kinase interactions varied continuously over a 100-fold range and provided a platform to study client protein recognition. In wild-type clients, HSP90 did not bind particular sequence motifs, but rather associated with intrinsically unstable kinases. Stabilization of the kinase in either its active or inactive conformation with diverse small molecules decreased HSP90 association. Our results establish HSP90 client recognition as a combinatorial process: CDC37 provides recognition of the kinase family, whereas thermodynamic parameters determine client binding within the family.
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“Hsp90 is required for the functional maturation of ~10% of the eukaryotic proteome, including signaling proteins such as GR, a steroid hormone receptor (SHR)1,3,13.”
From Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism (2022) · cites this paper as [3]
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In the citing paper
“Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of ‘client’ proteins1-3.”
From Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism (2022) · cites this paper as [3]
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In the citing paper
“Hsp90 ‘clients’ are enriched in signaling proteins, such as steroid hormone receptors (SHRs), making Hsp90 an important clinical target2–4.”
From Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor (2023) · cites this paper as [3]
In the citing paper
“The molecular chaperone Hsp90 plays a crucial role in protein homeostasis by regulating the folding and activity of a set of proteins known as clients (1–3).”
From Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network (2021) · cites this paper as [3]
In the citing paper
“Hsp90 promotes the maturation of a diverse array of metastable signal transduction proteins, including kinases, phosphatases, and ubiquitin ligases (known as Hsp90 clients) [32]. These function in many stress response pathways.”
From Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B (2013) · cites this paper as [32]
In the citing paper
“estimates suggesting that Hsp90 associates with more than one-half of the human kinome (Taipale et al., 2012”
From Functional Genomic Screening Reveals Core Modulators of Echinocandin Stress Responses in Candida albicans (2018) · cites this paper as Taipale et al., 2012
In the citing paper
“This is in contrast to other studies that identify only select kinases within a signaling cascade as Hsp90 clients (Taipale et al., 2012”
From Functional Genomic Screening Reveals Core Modulators of Echinocandin Stress Responses in Candida albicans (2018) · cites this paper as Taipale et al., 2012
In the citing paper
“Protein kinases are core transducers of cellular stress and a major class of Hsp90 client proteins”
From Functional Genomic Screening Reveals Core Modulators of Echinocandin Stress Responses in Candida albicans (2018) · cites this paper as Taipale et al., 2012
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Cites
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Metadata
- Authors
- Taipale, M., Krykbaeva, I., Koeva, M., Kayatekin, C., Westover, K. D., Karras, G. I., & Lindquist, S.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Lindquist, Susan
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 150
- Issue
- 5
- Pages
- 987-1001
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3894786
- OpenAlex
- W2096237314
- Cited by
- 879
- References
- 47
- Citations by year
- 2026: 49 · 2025: 59 · 2024: 59 · 2023: 61 · 2022: 55 · 2021: 48 · 2020: 78 · 2019: 55 · 2018: 77 · 2017: 59 · 2016: 70 · 2015: 72 · 2014: 75 · 2013: 53 · 2012: 6
- FWCI
- 26.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Elsevier eBooks
- Funders
- Howard Hughes Medical Institute
- National Human Genome Research Institute (RL1HG004671)
- National Cancer Institute (RL1CA133834)
- National Institute of General Medical Sciences (RL1GM084437)
- National Institute of Dental and Craniofacial Research (UL1DE019585)
- 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 › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- HSP90, Hsp90 client proteins, Cdc37, molecular chaperones, substrate recognition, protein-protein interaction, kinases, transcription factors, E3 ubiquitin ligase, small molecule inhibitors, binding thermodynamics
- MeSH terms
- Amino Acid Sequence, Animals, Humans, Models, Molecular, Molecular Sequence Data, Protein Kinases, Receptors, Steroid, Thermodynamics, Transcription Factors, Sequence Alignment, Cell Cycle Proteins, Chaperonins, HSP90 Heat-Shock Proteins, Proteome, Protein Interaction Mapping, Ubiquitin-Protein Ligases, Luciferases, Renilla, Protein Interaction Domains and Motifs, Protein Stability
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