Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase
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Abstract
Holding kinases at the ready: About 60% of kinases only reach their active state in the presence of the molecular chaperone Hsp90 and its co-chaperone Cdc37. It is unclear how the chaperones facilitate kinase function or why only some kinases are chaperone-dependent. Verba et al. determined a 3.9 Å cryo–electron microscopy structure of Hsp90:Cdc37 in complex with the kinase Cdk4. Together, Hsp90 and Cdc37 trap the kinase in an open, partially unfolded state. Taking on this state probably has direct functional benefits. Science , this issue p. 1542
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The Hsp90 client-binding residues Y528, Q531 and M610 contact the unfolded Cdk4 client in the closed-state Hsp90:Cdc37:Cdk4 structure.
“have been identified to contact the unfolded Cdk4 client in the Hsp90:Cdc37:Cdk4 closed state structure”
From The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state (2021) · cites this paper as Verba et al., 2016
The sections on Hsp90’s closed conformation and the unfolded Cdk4 N-lobe describe a closed Hsp90:Cdc37:Cdk4 complex in which Cdk4 contacts an Hsp90 client-binding site. They do not identify Y528, Q531, or M610 as the contacting residues; searches for those residue labels found no matching passage in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCryo-EM structures of client-bound Hsp90 show the client unfolds substantially, probably when the closed state forms.
“Cryo-EM structures of the client-bound Hsp90 reveal the client undergoes substantial unfolding, likely upon formation of the Hsp90 closed state”
From The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state (2021) · cites this paper as Verba et al., 2016
The Abstract and the sections on Hsp90’s closed conformation and the Cdk4 N-lobe describe a cryo-EM complex in which Hsp90 is closed and the kinase is substantially unfolded. They do not establish that unfolding occurs when Hsp90 closes; the section on linking kinase unfolding to assembly instead proposes that kinases sample an open state that encourages chaperone binding. Page numbers are not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn previously reported closed-state structures the CTD is widened even without a bound H7e, suggesting NTD dimerization alone may cause this.
“in existing closed state structures (Huck et al., 2017; Verba et al., 2016) the CTD adopts this widened conformation in the absence of a bound H7e moiety, indicating this may result from NTD dimerization alone”
From The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state (2021) · cites this paper as Verba et al., 2016
The section “Hsp90 is in a closed conformation in the complex” (page unavailable) reports a closed Hsp90 structure with a small CTD rotation. The Main Text says that the NTDs dimerize in the closed state. Neither passage establishes that the CTD is widened without bound H7e or that NTD dimerization alone causes that conformation. (LLM, conf=0.78)
Experimental — accuracy not yet measuredBoth clients are threaded through the closed Hsp90 lumen, suggesting a universal binding mode for Hsp90 clients.
“Both clients are threaded through the closed Hsp90 lumen, suggesting a universal binding mode for Hsp90 clients11,35”
From Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism (2022) · cites this paper as [11]
The section “The N-lobe of Cdk4 is significantly unfolded and threads through Hsp90” reports Cdk4 density passing through the Hsp90 lumen; “Hsp90 is in a closed conformation in the complex” establishes that Hsp90 is closed. This paper examines one client, Cdk4, and does not establish that both clients thread through the lumen or that this is a universal binding mode. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTwo hydrophobic residues may represent the common binding pattern of the Hsp90 client: I271 and I274 in AhR, L525 and L528 in GR, and V89 and V92 in Cdk4.
“we found that two hydrophobic residues may represent the common binding pattern of the Hsp90 client, which are I271 and I274 in AhR, L525 and L528 in GR,33 and V89 and V92 in Cdk428”
From Cryo-EM structure of the cytosolic AhR complex. (2023) · cites this paper as [28]
In “The N-lobe of Cdk4 is significantly unfolded and threads through Hsp90” (page unavailable), the paper reports hydrophobic interactions between Cdk4’s β5 strand and an Hsp90 client-binding site. It does not identify V89 and V92 as the interacting residues. In “Hsp90/Cdc37 capture and stabilize structural transitions within the kinase” (page unavailable), it proposes that kinase-client recognition depends on a propensity to unfold, rather than a specific binding sequence; the proposed common two-residue pattern is therefore not supported by this source. (LLM, conf=0.84)
Experimental — accuracy not yet measured
In the Hsp90:Cdc37:Cdk4 structure the Cdk4 N-lobe is unfolded and threaded through the middle-domain dimer cleft, exposing residues that would be buried when folded.
“The N-lobe of Cdk4 is unfolded and threaded though the MD dimer cleft in the Hsp90:Cdc37:Cdk4 structure exposing a strand of residues that would be inaccessible in the folded state”
From The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state (2021) · cites this paper as Verba et al., 2016
Experimental — accuracy not yet measuredThe native GR:Hsp90 structure contrasts with the unfolded kinase:Hsp90 structure.
“sharply contrasting with the unfolded kinase:Hsp90 structure11.”
From Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism (2022) · cites this paper as [11]
The kinase:Hsp90 structure showed how Hsp90 stabilizes an inactive client but did not explain how Hsp90 reactivates a client such as GR.
“The kinase:Hsp90 structure11 first revealed how Hsp90 can stabilize an inactive client, but provided no insights to explain how Hsp90 can reactivate a client, such as GR.”
From Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism (2022) · cites this paper as [11]
The active native GR in this complex contrasts with the only other closed Hsp90:client complex, which stabilizes an unfolded kinase client.
“The active, native GR in our complex starkly contrasts with the only other structure of a closed Hsp90:client complex, which stabilizes an unfolded kinase client11.”
From Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism (2022) · cites this paper as [11]
These findings support an emerging paradigm in which Hsp90 cochaperones make specific direct contact with Hsp90 clients to aid client recognition and function.
“These findings support an emerging paradigm in which Hsp90 cochaperones make specific, direct contact with Hsp90 clients to aid in client recognition and function11,12.”
From Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism (2022) · cites this paper as [11]
Sodium molybdate stabilizes Hsp90's closed conformation, probably by mimicking a gamma-phosphate to stabilize the post-ATP hydrolysis transition state.
“20 mM sodium molybdate (used to stabilize the closed conformation of Hsp9011,42,43, likely by acting as a γ-phosphate analog to stabilize the post-ATP hydrolysis transition state of Hsp90 (Extended Data Fig. 2c))”
From Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism (2022) · cites this paper as [11]
In the Hsp90:FKBP51:p23 structure, FKBP51 runs from its CTD-TPR contact along the Hsp90 middle domain, placing the N-terminal FK1 domain next to the sites where Hsp90 engages clients.
“In the Hsp90:FKBP51:p23 structure FKBP51 extends from the CTD-TPR interaction along the Hsp90 MD, enabling the N-terminal FK1 domain to be positioned adjacent Hsp90 client interaction sites”
From The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state (2021) · cites this paper as Verba et al., 2016
The sections on Cdc37 wrapping around Hsp90 and on Cdk4 binding describe an Hsp90:Cdc37:Cdk4 complex, including Hsp90 middle-domain and client contacts. Searches for FKBP51 and the proposed TPR-to-FK1 arrangement found no passage addressing FKBP51’s position in an Hsp90:FKBP51:p23 structure. The cited paper therefore does not verify the specific structural claim. (LLM, conf=0.77)
Experimental — accuracy not yet measuredCo-chaperones mediate client interaction, for example the kinase-specific Cdc37.
“and by mediating client interaction [e.g., the kinase-specific Cdc37 (5, 6)].”
From Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network (2021) · cites this paper as [6]
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- Authors
- Verba, K. A., Wang, R. Y.-R., Arakawa, A., Liu, Y., Shirouzu, M., Yokoyama, S., & Agard, D. A.
- Affiliations
- Howard Hughes Medical Institute (US)
- RIKEN (JP)
- Corresponding author
- Agard, David A.
- ORCID
- Venue
- Science
- Published
- 2016-06-24
- Volume
- 352
- Issue
- 6293
- Pages
- 1542-1547
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5373496
- OpenAlex
- W2467034934
- Semantic Scholar
- be9d874235bbeead8cd0fdf0f8296dc124cc3bd3
- Cited by
- 424
- References
- 58
- Citations by year
- 2026: 25 · 2025: 23 · 2024: 35 · 2023: 44 · 2022: 53 · 2021: 52 · 2020: 52 · 2019: 52 · 2018: 40 · 2017: 39 · 2016: 7
- FWCI
- 23.90
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Protein Structure Initiative-Biology (U01 GM098254)
- American Association for Cancer Research-Breast Cancer Research Foundation (218084)
- HHMI Helen Hay Whitney Foundation Fellowship
- HHMI International Student Research Fellowship
- HHMI
- NIH National Institute of General Medical Sciences (P41 GM103310)
- NSF (ACI-1053575)
- 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, Cdc37, CDK4, kinase activation, molecular chaperones, protein complex structure
- MeSH terms
- Animals, Enzyme Stability, Humans, Models, Molecular, Protein Structure, Secondary, Cell Cycle Proteins, Chaperonins, HSP90 Heat-Shock Proteins, Multiprotein Complexes, Cyclin-Dependent Kinase 4, Protein Unfolding, Sf9 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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