The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state
Open accessPublished version of a preprint
Abstract
The Hsp90 chaperone promotes folding and activation of hundreds of client proteins in the cell through an ATP-dependent conformational cycle guided by distinct cochaperone regulators. The FKBP51 immunophilin binds Hsp90 with its tetratricopeptide repeat (TPR) domain and catalyzes peptidyl-prolyl isomerase (PPIase) activity during folding of kinases, nuclear receptors, and tau. Here we determined the cryoelectron microscopy (cryo-EM) structure of the human Hsp90:FKBP51:p23 complex to 3.3 Å, which, together with mutagenesis and crosslinking analyses, reveals the basis for cochaperone binding to Hsp90 during client maturation. A helix extension in the TPR functions as a key recognition element, interacting across the Hsp90 C-terminal dimer interface presented in the closed, ATP conformation. The PPIase domain is positioned along the middle domain, adjacent to Hsp90 client binding sites, whereas a single p23 makes stabilizing interactions with the N-terminal dimer. With this architecture, FKBP51 is positioned to act on specific client residues presented during Hsp90-catalyzed remodeling.
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Claims the paper makes
2 of 6 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured
- Finding
A kinked H7 extension of FKBP51 makes a new binding interface across the Hsp90 CTD dimer that is larger than canonical MEEVD-only binding.
“Overall, the H7e region buries ~830 Å2 of CTD surface area, which is larger than what is estimated for MEEVD interaction (~500 Å2) (Kumar et al., 2017), thus revealing a new and substantial binding interface beyond the canonical TPR interaction.”
Quote in the paperNot yet classified1 of 1 sources checked- cites Kumar et al., 2017 sourceExperimental — accuracy not yet measured
- Finding
p23 preferentially binds the closed, ATP state of Hsp90 and is compatible with FKBP51 to form a ternary client-maturation complex.
“Thus, while the interaction appears to be low affinity with a possible 2:1 stoichiometry, this supports the known p23-specificity for the closed, ATP state of Hsp90 (Richter et al., 2004; Siligardi et al., 2004).”
Quote in the paperNot yet classified1 of 2 sources checked - Finding
The structure predicts that FKBP51's PPIase active site is positioned to catalyze isomerization of proline residues in unfolded or exposed client regions.
“the position of the FK1 domain in our structure appears positioned for catalyzing isomerization of proline residues localized in unfolded regions or adjacent sites that are optimally presented in the Hsp90-bound state of the client.”
Quote in the paperNot yet classified - Finding
Photocrosslinking shows the FK1 beta3 bulge is close to Hsp90 and crosslinks in a conformation-specific manner.
“D72Bpa, strong crosslinked bands are only present under the Hsp90-closed state condition, indicating that crosslinking at this position is conformation-specific.”
Quote in the paperNot yet classified - Finding
Residues Y409, M412, and F413 in FKBP51 H7e are conserved among immunophilin-class TPR cochaperones and likely represent a conserved Hsp90-recognition mechanism.
“The H7e itself, as well as residues Y409, M412, and F413 are conserved among the immunophilin-class of TPR cochaperones (Figure S5F). Thus, the interaction identified here likely represents a conserved Hsp90-specific recognition mechanism for these cochaperones.”
Quote in the paperNot yet classified
- Finding
Hsp90 and FKBP51 can engage in the open state, but that interaction is lower affinity than in the closed state.
“Based on our SEC-MALS and FP data we do identify binding between FKBP51 and Hsp90 in the open state, but with a substantially lower affinity.”
Quote in the paperNot yet classified - Finding
The TPR:EEVD interaction alone is insufficient for stable Hsp90-FKBP51 complex formation, and H7e is required for state discrimination.
“These results are in agreement with the SEC-MALS data and establish that FKBP51 has a higher affinity for Hsp90 in the closed, ATP compared to open state. Furthermore, the H7e interaction indeed functions as a key component of the Hsp90 closed-state interaction.”
Quote in the paperNot yet classified - Finding
Deleting H7e or mutating M412 or F413 weakens or abolishes FKBP51 binding to Hsp90 in the closed state.
“Truncation of H7e from position H401 (ΔH7e) substantially reduced FKBP51 binding to Hsp90 under closed-state conditions”
Quote in the paperNot yet classified - Finding
The Hsp90:FKBP51:p23 complex has an asymmetric 2:1:1 arrangement with one FKBP51 and one p23 bound to an Hsp90 dimer.
“revealing an asymmetric 2:1:1 arrangement”
Quote in the paperNot yet classified - Finding
FKBP51 binds Hsp90 more stably in the closed, ATP state and forms an approximately 2:1 complex.
“These results therefore indicate that FKBP51 more stably binds the closed, ATP conformation of Hsp90, forming a 2:1 asymmetric complex.”
Quote in the paperNot yet classified - Finding
The authors propose that FKBP51 acts specifically during the client maturation step after client loading and NTD dimerization.
“we propose a model in which FKBP51 acts specifically during the client maturation step, binding Hsp90 in the ATP-bound state following client loading and NTD dimerization”
Quote in the paperNot yet classified - Finding
Hsp90 and FKBP51 bind more weakly in the open state than in the closed state, with closed-state competition showing higher affinity.
“From these experiments, Ki values were determined to be 0.9 and 3.0 μM for the closed and open states, respectively, revealing a ~3.3-fold increase in affinity when Hsp90 is in the closed-state conformation”
Quote in the paperNot yet classified - Finding
The FK1 domain is positioned adjacent to Hsp90 client-binding sites in the closed complex, suggesting it can act on Hsp90-bound clients.
“enabling the N-terminal FK1 domain to be positioned adjacent Hsp90 client interaction sites”
Quote in the paperNot yet classified - Finding
In the closed-state complex, FKBP51 binds Hsp90 mainly through its TPR domain, with the TPR helix 7 extension contacting the Hsp90 C-terminal dimer interface.
“the TPR domain of FKBP51 is oriented with the MEEVD binding pocket positioned away from the Hsp90 CTD”
Quote in the paperNot yet classified - Finding
The cryo-EM structure of the human Hsp90:FKBP51:p23 complex was determined to 3.3 Å and reveals the basis for cochaperone binding during client maturation.
“Here we have determined the cryo-EM structure of the human Hsp90:FKBP51:p23 complex to 3.3 Å that, together with mutagenesis and crosslinking analysis, reveals the basis for cochaperone binding to Hsp90 during client maturation.”
Quote in the paperNot yet classified - Method
The study used cryo-EM, SEC-MALS, native gels, fluorescence polarization, and Bpa crosslinking to characterize Hsp90-FKBP51 interactions.
“Initial screening by cryo-EM indicated the complex is unstable, likely due to the vitrification conditions.”
Quote in the paperNot yet classified0 of 1 sources checked- cites Southworth and Agard, 2011 source
- Method
The authors deposited cryo-EM maps and atomic coordinates in public databases.
“Cryo-EM densities have been deposited at the Electron Microscopy Data Bank under accession codes EMD: 23213 (Hsp90:FKBP51:p23 closed-state complex) and EMD: 23214 (Hsp90:p23 closed-state complex). Atomic coordinates have been deposited at the Protein Data Bank under accession codes PDB: 7L7I (Hsp90:FKBP51:p23 closed-state complex) and PDB: 7L7J (Hsp90:p23 closed-state complex).”
Quote in the paperNot yet classified - Method
Human Hsp90 closed-state formation was promoted by high salt, higher temperature, and AMPPNP.
“both high temperature and salt concentration are required along with AMPPNP in order to promote a complete mobility shift”
Quote in the paperNot yet classified - Method
The authors stabilized the complex for cryo-EM by low-level glutaraldehyde crosslinking after complex formation.
“samples were diluted and crosslinked by low-level (0.01%) glutaraldehyde crosslinking in 100 mM KCl after the complex formation”
Quote in the paperNot yet classified0 of 1 sources checked- cites Southworth and Agard, 2011 source
- Background
Hsp90 forms dynamic assemblies with cochaperones that regulate its ATPase cycle and client folding steps.
“Hsp90 forms dynamic macromolecular assemblies with distinct cochaperone proteins that regulate its ATPase cycle and client folding steps”
Quote in the paperNot yet classified0 of 1 sources checked- cites Pearl and Prodromou, 2006 source
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Based on FKBP52TPR being sufficient to bind Hsp90 and Hsp90:SHR complexes, the FKBP52 single point mutants probably do not disrupt FKBP52 binding to the GR:Hsp90 complex, but specifically disrupt the GR:FKBP52 interaction and prevent stabilization of GRLBD by FKBP52.
“Based on the observation that FKBP52TPR is sufficient to bind Hsp90 and Hsp90:SHR complexes19,20, the FKBP52 single point mutants probably do not disrupt FKBP52 binding to the GR:Hsp90 complex, but specifically disrupt the GR:FKBP52 interaction and prevent stabilization of GRLBD by FKBP52.”
From Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor (2023) · cites this paper as [19]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredPrevious reports showed FKBP51 and p23 could simultaneously bind the closed Hsp90 in the absence of client.
“Previous reports showed FKBP51 and p23 could simultaneously bind the closed Hsp90 in the absence of client19.”
From Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor (2023) · cites this paper as [19]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Negative-stain methods reverse the assigned open and closed conditions
MinorThe negative-stain methods assign the open state to AMPPNP treatment and the closed state to its absence. The results assign those states the other way around.
“in the presence or absence of 2 mM AMPPNP at 37°C to form the open and closed states, respectively.”
“In the absence of AMPPNP, Hsp90 particles adopt an open, extended conformation reflective of the apo state, similar to previous studies (Southworth and Agard, 2008). Conversely, analysis of Hsp90 incubated with AMPPNP and high salt at 37°C reveals the particles shift to a closed conformation”
K2 frame count does not match its exposure time
MinorAt 0.05 seconds per frame, 120 frames span 6 seconds, not the reported 8-second K2 exposure. The stated 6-second K3 exposure does match 120 frames.
Reported 8 · recomputed 6
“for total 8 and 6 seconds exposures at 0.05 s/frame in 120 frames”
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- Authors
- Lee, K., Thwin, A. C., Nadel, C. M., Tse, E., Gates, S. N., Gestwicki, J. E., & Southworth, D. R.
- Affiliations
- University of California, San Francisco (US)
- University of Michigan (US)
- Corresponding author
- Southworth, Daniel R.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 81
- Issue
- 17
- Pages
- 3496-3508.e5
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC8418782
- OpenAlex
- W3187889591
- Cited by
- 76
- References
- 82
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 12 · 2023: 20 · 2022: 16 · 2021: 4
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- University of California, San Francisco
- National Institutes of Health (AG002132)
- National Institute on Aging (AG068125)
- Alzheimer's Association
- 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 › Signaling Pathways in Disease
- Keywords
- HSP90, FKBP51, immunophilins, p23, tetratricopeptide repeat domain, peptidyl-prolyl isomerase, protein folding, kinase activation, cryo-EM structure
- MeSH terms
- Tumor Protein, Translationally-Controlled 1, Tacrolimus Binding Protein 5, Amino Acid Sequence, Binding Sites, Humans, Molecular Conformation, Protein Binding, Biomarkers, Tumor, Molecular Chaperones, HSP90 Heat-Shock Proteins, Cryoelectron Microscopy, Tacrolimus Binding Proteins
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.
Claims read (extract-v1) on 2026-09-25.
Cited sources are checked by gpt-6-sol.
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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