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Cited by 59Heat shock proteins researchProtein Structure and DynamicsUbiquitin and proteasome pathways

Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network

Open access
Lopez, Abraham, Dahiya, Vinay, Delhommel, Florent, Freiburger, Lee, Stehle, Ralf, Asami, Sam, Rutz, Daniel, Blair, Laura +2 more·2021·Science Advances
DOI 10.1126/sciadv.abl7295PMC PMC8682993
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Abstract

ATP-driven conformational selection of Hsp90 conformations modulates the binding of clients and co-chaperones.

AI snapshot

Written from the paper’s full text.

TL;DR

ATP binding to full-length yeast Hsp90 shifts a minor NTD-rotated conformation without substantially closing the dimer, and client binding can further shift this conformational equilibrium through an allosteric network. GR-LBD preferentially selects and stabilizes the NTD-rotated/closed state, whereas MR-LBD, p53-DBD, and Tau show weaker or conformation-independent binding.

Key findings

  • ATP binding induces a minor Hsp90 conformational state with an NTD-rotated arrangement populated at ≈20%, in slow exchange with the major open state; the A107N mutant increases this population to ≈50%.
  • GR-LBD binding shifts the NTD-rotated population from ≈20% to ≈55%, increases affinity for ATP-bound Hsp90 (K_D 2.8 ± 0.23 μM apo vs. 0.9 ± 0.11 μM ATP), and reduces Hsp90 ATPase activity by 50%.
  • MR-LBD binds better to ATP analogs (K_D 5.7 ± 0.38 μM apo vs. 2.2 ± 0.25 μM AMP-PNP and 1.9 ± 0.06 μM ATPγS) but does not significantly shift the NTD-rotated population; p53-DBD and Tau bind with similar low-micromolar affinities independent of nucleotide state.
  • p23 stabilizes the NTD-rotated state, increasing its population from ≈20% to ≈35%, and forms ternary complexes with Hsp90-ATP and clients; SAXS shows GR-LBD compacts Hsp90-ATP (R_g 61.3 Å to 58.8 Å), while p53-DBD and Tau cause only minor changes.

Methods

  • Combined methyl NMR spectroscopy (AILVM pro-R labeling), small-angle X-ray scattering (SAXS), ensemble optimization modeling (EOM), circular dichroism, ANS fluorescence, fluorescence anisotropy, analytical ultracentrifugation, and ATPase assays.
  • Used full-length yeast Hsp90 (Hsp82) and clients GR-LBD, MR-LBD, p53-DBD, and Tau isoform D, plus p23 and Hsp90 mutants R32A, R380A, and A107N.
  • Analyzed chemical shift perturbations, paramagnetic relaxation enhancements, NMR signal intensities to derive conformational populations, SAXS P(r)/R_g, client binding affinities, and ATPase rates.

Limitations

  • The paper does not include a dedicated Limitations section. Stated caveats include that Hsp90-client complexes are dynamic and challenging for structural analysis, that remaining differences between experimental and back-calculated PREs likely indicate additional intermediate conformations, and that Tau shows weak/transient interactions at multiple sites.
  • Evident from the text: the study is in vitro with yeast Hsp90 and a selected set of four clients, so generalization to other clients, co-chaperone combinations, or cellular conditions is not established; MR-LBD effects are smaller and the authors note they may reflect weaker binding or different client dynamics rather than a clearly resolved mechanism.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1126/sciadv.abl7295

Cites

95 of 95 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 62 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The presence of ATP results in large spectral changes.

    “The presence of ATP results in large spectral changes (Fig. 2B and fig. S3A).”
    Quote in the paperSubstantial claim
  • Findingown data

    SAXS data of apo-Hsp90 are consistent with an ensemble of extended structures, indicated by a population-averaged Rg of 62.3 Å.

    “SAXS data of apo-Hsp90 are consistent with an ensemble of extended structures, indicated by a population-averaged Rg of 62.3 Å (Fig. 2A and table S1).”
    Quote in the paperSubstantial claim
  • Findingown data

    ATP binding results only in a minor compaction of Hsp90 (Rg of 57.6 Å).

    “Unexpectedly, ATP binding results only in a minor compaction of Hsp90 (Rg of 57.6 Å).”
    Quote in the paperSubstantial claim
  • Findingown data

    A minor conformational state with a population of about 20% is in slow exchange (kex < 1000 s−1) with the major species.

    “The presence of these additional signals is indicative of a minor conformational state with a population of about ≈20% on the basis of the NMR signal integration that is in slow exchange (on the chemical shift time scale, i.e., kex < 1000 s−1) with the major species.”
    Quote in the paperSubstantial claim
  • Findingown data

    For the GR-LBD, the affinity significantly increases in the Hsp90-ATP state.

    “For the GR-LBD, the affinity significantly increases in the Hsp90-ATP state, while MR shows enhanced binding in the presence of ATP analogs [AMP-PNP and adenosine 5′-[γ-thio]triphosphate (ATPγS)].”
    Quote in the paperSubstantial claim
  • May combine two claims. 54
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Findingown data

    The minor conformational state is observed in both the full-length Hsp90 dimer and a monomeric NTD-MD construct in the presence of AMP-PNP, but not in the isolated NTD.

    “Notably, the minor conformational state is observed in both the full-length Hsp90 dimer and a monomeric NTD-MD construct in the presence of adenylyl-imidodiphosphate (AMP-PNP), but not in the isolated NTD (fig. S3, B to D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ensembles containing ≈20% of rotated NTD-MD arrangement describe the experimental scattering profile with highest agreement and are consistent with the NMR-derived populations.

    “As seen in fig. S2B, ensembles containing ≈20% of rotated NTD-MD arrangement describe the experimental scattering profile with highest agreement and are consistent with the NMR-derived populations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Experimental PREs of the major state correlate well with values back-calculated for the open dimer and are inconsistent with the closed state.

    “The experimental PREs of the major state correlate well with the values back-calculated for the structure of the open dimer (Fig. 3E and fig. S4, A and B) and are inconsistent with the values back-calculated from the closed state, indicating that the major states correspond to the nonrotated NTD-MD arrangement.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Only GR binding to Hsp90 causes a 50% reduction of the ATPase activity of Hsp90, while the other clients tested do not affect the Hsp90 ATPase rate.

    “We tested this for all clients and found that only GR binding to Hsp90 causes a 50% reduction of the ATPase activity of Hsp90 (Fig. 5B), while the other clients tested do not affect the Hsp90 ATPase rate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tau is devoid of stable secondary structures, and thermal unfolding is not cooperative.

    “As expected for an IDP, Tau is devoid of stable secondary structures, and thermal unfolding is not cooperative.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    AUC experiments show that ATP favors complex formation for the GR-LBD, while Hsp90-MR-LBD complexes are enhanced in the presence of ATP analogs, and no effects of nucleotides were observed for the p53-DBD and Tau.

    “Here, ATP favors complex formation in the case of the GR-LBD, while the Hsp90–MR-LBD complexes are enhanced in the presence of ATP analogs. In contrast, no effects of nucleotides were observed for the p53-DBD and Tau.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    MR-LBD, p53-DBD, and Tau cause smaller spectral changes upon binding Hsp90 than GR-LBD.

    “Smaller spectral changes are seen upon binding of MR-LBD, p53-DBD, and Tau.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    p23 interactions directly affect residues in the ATP lid and N-terminal region of helix Mα2 and extend to the secondary dimerization region, NTD-MD interface, and Cα2 at the client binding site (I320 and M589).

    “The p23 interactions directly affect residues in the ATP lid and the N-terminal region of helix Mα2 (fig. S11A) and extend to the secondary dimerization region, the NTD-MD interface, and the Cα2 at the client binding site (residues I320 and M589, respectively; Fig. 8B and fig. S12B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    p53-DBD and Tau elicit overall small changes in the NMR spectra of Hsp90 and do not affect the population of the NTD-rotated state.

    “As expected, p53-DBD and Tau, whose binding are not affected by nucleotides, elicit overall small changes in the NMR spectra of Hsp90 and do not affect the population of the NTD-rotated state (Fig. 7B and fig. S9C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    GR-LBD causes perturbations exclusive for the NTD-rotated conformation and significantly increases its population from ≈20% to ≈55%.

    “When we analyzed NMR spectral changes and the population of the NTD-rotated state in the presence of the GR-LBD, we observed perturbations exclusive for the rotated conformation, which are accompanied by a significant increase in its population (≈20 to ≈55%) (Fig. 7, A and B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Folded clients (GR, MR, and p53) bind to large and continuous surfaces, being more extensive in the case of SHRs.

    “Folded clients (GR, MR, and p53) bind to large and continuous surfaces, being more extensive in the case of SHRs (table S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Effects occur in all three Hsp90 domains, with stronger changes induced by the GR-LBD, smaller ones by the MR-LBD as well as the p53-DBD, and weak effects by Tau.

    “Notably, effects occur in all three Hsp90 domains, with stronger changes induced by the GR-LBD, smaller ones by the MR-LBD as well as the p53-DBD, and weak effects by Tau.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MR-LBD causes smaller spectral changes in distant regions and does not significantly change the population of the NTD-rotated conformation.

    “In contrast, the MR-LBD causes smaller spectral changes in distant regions and does not significantly change the population of the NTD-rotated conformation (Fig. 7, A and B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    p53-DBD and Tau do not affect Hsp90 ATPase activity and bind with similar affinities independent of the nucleotide state of the chaperone.

    “These clients do not affect the Hsp90 ATPase activity and bind with similar affinities independent of the nucleotide state of the chaperone (Fig. 9).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    NMR data reveal allosteric effects and the presence of two conformational states in these regions of Hsp90 in the presence of ATP, which are further influenced by client binding.

    “In exquisite agreement, our NMR data reveal allosteric effects and the presence of two conformational states in these regions of Hsp90 in the presence of ATP, which are further influenced by client binding.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ternary complexes sediment at 8 to 8.2S, while Hsp90-client complexes sediment at 6.2S.

    “The ternary complexes sediment at 8 to 8.2S, while Hsp90-client complexes sediment at 6.2S (Fig. 8F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Addition of MR-LBD to Hsp90 in the absence of p23 only perturbs signals at the binding site (M589) and does not affect residues at the NTD-MD interface (I320).

    “In contrast, addition of MR-LBD to Hsp90 in the absence of p23 only perturbs signals at the binding site (M589) and does not affect residues at the NTD-MD interface, i.e., I320 (Fig. 8E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    p53-DBD and Tau do not interact with the Cα2 helix and do not induce substantial allosteric changes.

    “In contrast, p53-DBD and Tau, which do not interact with the Cα2 helix, do not induce substantial allosteric changes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Generally used, conserved binding sites are located at the internal MD-CTD interface of the open Hsp90 dimer and are shared by all clients studied, with additional contributions from the ATP lid.

    “Generally used, conserved binding sites are located at the internal MD-CTD interface of the open Hsp90 dimer and are shared by all clients studied, with additional contributions from the ATP lid.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    These sites are extended and harbor short amphipathic binding motifs: 423KNIKLG428, 505IDEY508, 554LKEIL558, and 589MERIM593.

    “These sites are extended and harbor short amphipathic binding motifs, i.e., 423KNIKLG428, 505IDEY508, 554LKEIL558, and 589MERIM593, which, in part, have been implicated in client binding in vivo (60–62).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [60] S. P. Bohen, K. R. Yamamoto, Isolation of Hsp90 mutants by screening for decreased steroid receptor function. Proc. Natl. Acad. Sci. U.S.A. 90, 11424– 11428 (1993). 8248264 PMC47995 source

      Not checked in the free run.

    • cites [61] L. Fang, D. Ricketson, L. Getubig, B. Darimont, Unliganded and hormone-bound glucocorticoid receptors interact with distinct hydrophobic sites in the Hsp90 C-terminal domain. Proc. Natl. Acad. Sci. U.S.A. 103, 18487– 18492 (2006). 17130446 PMC1693689

      Not checked in the free run.

    • cites [62] O. Genest, M. Reidy, T. O. Street, J. R. Hoskins, J. L. Camberg, D. A. Agard, D. C. Masison, S. Wickner, Uncovering a region of heat shock protein 90 important for client binding in E. coli and chaperone function in yeast. Mol. Cell 49, 464– 473 (2013). 23260660 PMC3570620 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Clients are readily able to displace the p23 C-terminal tail, which then binds and stabilizes the bound client.

    “Our data show that clients are readily able to displace the p23 C-terminal tail, which then bind and stabilize to the bound client.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hsp90 is selective for certain types of clients, including transcription factors, kinases, and intrinsically disordered proteins.

    “Distinct from other chaperones, Hsp90 is selective for certain types of clients, including transcription factors, kinases, or even intrinsically disordered proteins (IDPs) (www.picard.ch/Hsp90Int/).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites www.picard.ch/Hsp90Int/

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Hsp90 plays a crucial role in protein homeostasis by regulating the folding and activity of a set of proteins known as clients.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] A. J. McClellan, Y. Xia, A. M. Deutschbauer, R. W. Davis, M. Gerstein, J. Frydman, Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approaches. Cell 131, 121– 135 (2007). 17923092

      Not checked in the free run.

    • cites [2] D. F. Nathan, M. H. Vos, S. Lindquist, In vivo functions of the Saccharomyces cerevisiae Hsp90 chaperone. Proc. Natl. Acad. Sci. U.S.A. 94, 12949– 12956 (1997). 9371781 PMC24244 source

      Not checked in the free run.

    • cites [3] M. Taipale, I. Krykbaeva, M. Koeva, C. Kayatekin, K. D. Westover, G. I. Karras, S. Lindquist, Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 150, 987– 1001 (2012). 22939624 PMC3894786 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The GR-LBD preferentially binds to a specific conformation of Hsp90 during the ATPase cycle, consistent with the about sixfold higher affinity for the ATP-bound state and the effects on ATPase activity.

    “Overall, our experiments show that the GR-LBD preferentially binds to a specific conformation of Hsp90 during the ATPase cycle, which is consistent with the about sixfold higher affinity for the ATP-bound state and the effects on ATPase activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Combined NMR and SAXS analysis indicates that ATP binding triggers coordinated motions involving ATP lid closing, NTD rotation, and MD association, without substantially affecting the overall closure of the Hsp90 dimer.

    “In summary, the combined analysis by NMR and SAXS indicates that ATP binding triggers coordinated motions involving ATP lid closing, NTD rotation, and MD association, without substantially affecting the overall closure of the Hsp90 dimer.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Co-chaperones bind to Hsp90 and modulate its conformational states and activity.

    “Co-chaperones play an important role in these functions, by binding to Hsp90 and modulating its conformational states and activity (4)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] P. Sahasrabudhe, J. Rohrberg, M. M. Biebl, D. A. Rutz, J. Buchner, The plasticity of the Hsp90 Co-chaperone system. Mol. Cell 67, 947– 961.e5 (2017). 28890336 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Nucleotide binding stabilizes the NTD-rotated conformation, which resembles the interdomain arrangement seen in the fully closed Hsp90 dimer.

    “Thus, in the absence of nucleotide, the major conformation represents the open, nonrotated NTD-MD arrangement, while nucleotide binding stabilizes the NTD-rotated conformation, which resembles the interdomain arrangement seen in the fully closed Hsp90 dimer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The local NTD-MD rotation affects ≈20% of the Hsp90 molecules, resulting in allosteric changes that propagate across all domains including the client binding sites.

    “This local NTD-MD rotation affects ≈20% of the Hsp90 molecules, resulting in allosteric changes that propagate across all domains including the client binding sites (Fig. 3G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The minor conformation originates from changes in the NTD-MD arrangement depending on contacts between the two domains and excludes a potential trans-protomer effect in the full-length Hsp90 dimer.

    “This suggests that the minor conformation originates from changes in the NTD-MD arrangement depending on contacts between the two domains and excludes a potential trans-protomer effect in the full-length Hsp90 dimer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    R32A and R380A mutations disrupt NTD-MD contacts.

    “we selected previously characterized mutants that either disrupt [R32A (34) and R380A (35)] or stabilize [A107N (26)] NTD-MD contacts.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] S. L. Mader, A. Lopez, J. Lawatscheck, Q. Luo, D. A. Rutz, A. P. Gamiz-Hernandez, M. Sattler, J. Buchner, V. R. I. Kaila, Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90. Nat. Commun. 11, 1410 (2020). 32179743 PMC7075974

      Not checked in the free run.

    • cites [35] P. Meyer, C. Prodromou, B. Hu, C. Vaughan, S. M. Roe, B. Panaretou, P. W. Piper, L. H. Pearl, Structural and functional analysis of the middle segment of hsp90: Implications for ATP hydrolysis and client protein and cochaperone interactions. Mol. Cell 11, 647– 658 (2003). 12667448 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Co-chaperones mediate client interaction, for example the kinase-specific Cdc37.

    “and by mediating client interaction [e.g., the kinase-specific Cdc37 (5, 6)].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] D. Keramisanou, A. Aboalroub, Z. Zhang, W. Liu, D. Marshall, A. Diviney, R. W. Larsen, R. Landgraf, I. Gelis, Molecular mechanism of protein kinase recognition and sorting by the Hsp90 kinome-specific cochaperone Cdc37. Mol. Cell 62, 260– 271 (2016). 27105117 PMC4868553

      Not checked in the free run.

    • cites [6] K. A. Verba, R. Y. Wang, A. Arakawa, Y. Liu, M. Shirouzu, S. Yokoyama, D. A. Agard, Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science 352, 1542– 1547 (2016). 27339980 PMC5373496 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Species-dependent differences exist for the relative population of Hsp90 conformational states across Hsp90 orthologs.

    “While the overall structure and topology of Hsp90 is highly conserved in eukaryotes, species-dependent differences exist for the relative population of Hsp90 conformational states across Hsp90 orthologs (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] D. R. Southworth, D. A. Agard, Species-dependent ensembles of conserved conformational states define the Hsp90 chaperone ATPase cycle. Mol. Cell 32, 631– 640 (2008). 19061638 PMC2633443

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The presence of ATP and co-chaperones induces the formation of more compact structures, in which the NTD and MD are associated.

    “The presence of ATP and co-chaperones induces the formation of more compact structures, in which the NTD and MD are associated (13), as seen in a crystal structure of nucleotide-bound Hsp90.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] M. Hessling, K. Richter, J. Buchner, Dissection of the ATP-induced conformational cycle of the molecular chaperone Hsp90. Nat. Struct. Mol. Biol. 16, 287– 293 (2009). 19234467

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The N-terminal domain (NTD; residues 1 to 210 in yeast Hsp90) is responsible for ATP binding and harbors dynamic elements that respond to nucleotide binding.

    “The N-terminal domain (NTD; residues 1 to 210 in yeast Hsp90) is responsible for adenosine triphosphate (ATP) binding and harbors several dynamic elements that respond to nucleotide binding (7, 8).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] M. M. Ali, S. M. Roe, C. K. Vaughan, P. Meyer, B. Panaretou, P. W. Piper, C. Prodromou, L. H. Pearl, Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 440, 1013– 1017 (2006). 16625188 PMC5703407 source

      Not checked in the free run.

    • cites [8] C. Prodromou, S. M. Roe, P. W. Piper, L. H. Pearl, A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone. Nat. Struct. Biol. 4, 477– 482 (1997). 9187656

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    p53-DBD and Tau do not show increased binding to nucleotide-bound forms of Hsp90, demonstrating that they bind in a conformation-independent manner.

    “In contrast, p53-DBD and Tau do not show increased binding to nucleotide-bound forms of Hsp90, demonstrating that they bind in a conformation-independent manner.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    p23 stabilizes bound clients.

    “stabilizes bound clients (56).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Y. Morishima, K. C. Kanelakis, P. J. M. Murphy, E. R. Lowe, G. J. Jenkins, Y. Osawa, R. K. Sunahara, W. B. Pratt, The Hsp90 cochaperone p23 is the limiting component of the multiprotein Hsp90/Hsp70-based chaperone system in vivo where it acts to stabilize the client protein·Hsp90 complex. J. Biol. Chem. 278, 48754– 48763 (2003). 14507910

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    p23 inhibits Hsp90 ATPase activity.

    “inhibits its ATPase activity (54, 55)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] K. Richter, S. Walter, J. Buchner, The co-chaperone Sba1 connects the ATPase reaction of Hsp90 to the progression of the chaperone cycle. J. Mol. Biol. 342, 1403– 1413 (2004). 15364569 source

      Not checked in the free run.

    • cites [55] G. Siligardi, B. Hu, B. Panaretou, P. W. Piper, L. H. Pearl, C. Prodromou, Co-chaperone regulation of conformational switching in the Hsp90 ATPase cycle. J. Biol. Chem. 279, 51989– 51998 (2004). 15466438 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Direct interactions have been reported for the p23 tail and p53.

    “direct interactions have been previously reported for the p23 tail and p53 (24).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] A. Rehn, E. Moroni, B. K. Zierer, F. Tippel, G. Morra, C. John, K. Richter, G. Colombo, J. Buchner, Allosteric regulation points control the conformational dynamics of the molecular chaperone Hsp90. J. Mol. Biol. 428, 4559– 4571 (2016). 27663270

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Similar interactions are observed in a cryo-EM structure of the maturation complex of GR-Hsp90-p23.

    “Similar interactions are observed in a cryo-EM structure of the maturation complex of GR-Hsp90-p23 (18), and direct interactions have been previously reported for the p23 tail and p53 (24).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] C. M. Noddings, R. Y.-R. Wang, D. A. Agard, GR chaperone cycle mechanism revealed by cryo-EM: Reactivation of GR by the GR:Hsp90:p23 client-maturation complex. bioRxiv 2020.09.12.294975 [Preprint]. 13 September 2020; 10.1101/2020.09.12.294975.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The p23 tail contains a helical segment that weakly interacts with the MD-CTD interface of Hsp90 and with GR, free or in complex with Hsp90.

    “We have recently demonstrated that the p23 tail contains a helical segment that weakly interacts with the MD-CTD interface of Hsp90 and with GR, free or in complex with Hsp90 (57).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] M. Biebl, A. Lopez, A. Rehn, L. Freiburger, J. Lawatscheck, B. Blanck, M. Sattler, J. Buchner, Elements in the flexible tail of the co-chaperone p23 coordinate client binding and progression of the Hsp90 chaperone cycle 90-binding agent geldanamycin. Nat. Commun. 12, 828 (2021). 33547294 PMC7864943 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The MR-LBD shows enhanced binding in the presence of ATP analogs and no effects on ATPase activity; the specific Hsp90 conformations with which MR interacts seem to differ from those for GR.

    “The MR-LBD shows enhanced binding in the presence of ATP analogs and no effects on ATPase activity. Thus, the specific Hsp90 conformations with which they interact seem to differ.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    GR-LBD binds preferentially to the NTD-rotated state and shifts the conformational equilibrium of the Hsp90 dimer toward closed conformations.

    “This demonstrates that the GR-LBD binds preferentially to the NTD-rotated state and thereby further shifts the conformational equilibrium of the dimer toward closed conformations (Fig. 7, B and C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Both p53-DBD and Tau bind independently of the overall conformation of Hsp90 and show no allosteric effects on Hsp90.

    “Notably, both p53-DBD and Tau bind independently of the overall conformation of Hsp90 and show no allosteric effects on Hsp90.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The client interactions identified by the NMR data are located in regions that are buried in closed conformations, indicating that initial interaction occurs with open states.

    “The client interactions identified by the NMR data are located in regions that are buried in closed conformations, indicating that initial interaction occurs with open states (fig. S7A).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    p23 affects the processing of all client proteins.

    “p23 is special as it affects the processing of all client proteins, for which a detailed analysis has been performed (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] P. Sahasrabudhe, J. Rohrberg, M. M. Biebl, D. A. Rutz, J. Buchner, The plasticity of the Hsp90 Co-chaperone system. Mol. Cell 67, 947– 961.e5 (2017). 28890336 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Assignments were obtained for 185 methyl groups corresponding to 87% of all AILVM methyl groups and more than 25% of Hsp90 sequence, covering all domains and disordered elements.

    “Assignments were obtained for 185 methyl groups corresponding to 87% of all AILVM methyl groups and more than 25% of Hsp90 sequence, covering all domains and disordered elements (fig. S1A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    GR-LBD binding to the NTD-rotated state leads to a population shift of the NTD-MD arrangement toward the NTD-rotated state and increases dimer closing involved in ATP hydrolysis.

    “GR-LBD binding to the NTD-rotated state leads to a population shift of the NTD-MD arrangement toward the NTD-rotated state and thereby increases dimer closing involved in ATP hydrolysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Increased binding of GR-LBD to A107N and lower binding to R32A are consistent with a preferential binding to the ATP-induced rotated state.

    “As seen in Fig. 5C, increased binding of GR-LBD to A107N and lower binding to R32A are consistent with a preferential binding to the ATP-induced rotated state, while the absence of effects for the p53-DBD reflect conformation-independent binding.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    GR-LBD interactions with the NTD-rotated conformation of the Cα2 helix result in stabilization of this state and stalling of the fully closed, N-terminally dimerized state required for ATP hydrolysis.

    “Thus, GR-LBD interactions with the NTD-rotated conformation of this helix, indicated by specific NMR spectral changes, result in the stabilization of this state and stalling of the fully closed, N-terminally dimerized state required for ATP hydrolysis (Fig. 7) (4, 16).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] P. Sahasrabudhe, J. Rohrberg, M. M. Biebl, D. A. Rutz, J. Buchner, The plasticity of the Hsp90 Co-chaperone system. Mol. Cell 67, 947– 961.e5 (2017). 28890336 source

      Not checked in the free run.

    • cites [16] O. R. Lorenz, L. Freiburger, D. A. Rutz, M. Krause, B. K. Zierer, S. Alvira, J. Cuellar, J. M. Valpuesta, T. Madl, M. Sattler, J. Buchner, Modulation of the Hsp90 chaperone cycle by a stringent client protein. Mol. Cell 53, 941– 953 (2014). 24613341 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    For GR-LBD, p23 binding does not induce further spectral changes and merely binds to the conformation already selected by the client.

    “In the case of the GR-LBD, where client binding already strongly promotes dimer closing (Fig. 7), p23 binding does not induce further spectral changes and thus merely binds to the conformation that is already selected by the client (Fig. 8D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Addition of p23 causes additional chemical shift changes for I320 that resemble those observed for GR/p23, indicating that p23 stabilizes and increases the population of closed conformations of Hsp90 bound to MR.

    “The addition of p23 causes additional chemical shift changes for I320 that resemble those observed for GR/p23. This indicates that p23 stabilizes and increases the population of closed conformations of Hsp90 bound to MR.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    p23 stabilizes the closed state and promotes allosteric changes to the client binding sites of Hsp90.

    “In summary, these results indicate that p23 stabilizes the closed state and promotes allosteric changes to the client binding sites of Hsp90.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The region around W300 harbors conserved Y293, a phosphorylation site affecting Hsp90's structural dynamics and involved in the acceleration effect of Aha1 on Hsp90 closing.

    “This region also harbors the conserved Y293, a phosphorylation site affecting Hsp90’s structural dynamics and involved in the acceleration effect of Aha1 on Hsp90 closing (64).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] W. Xu, K. Beebe, J. D. Chavez, M. Boysen, Y. Lu, A. D. Zuehlke, D. Keramisanou, J. B. Trepel, C. Prodromou, M. P. Mayer, J. E. Bruce, I. Gelis, L. Neckers, Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1. Nat. Commun. 10, 2574 (2019). 31189925 PMC6561935

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The rotated NTD-MD arrangement requires conformational changes of the ATP lid and enables contacts with the MD required for ATP hydrolysis.

    “This rotated NTD-MD arrangement requires conformational changes of the ATP lid and enables contacts with the MD required for ATP hydrolysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These changes lead to N-terminal dimerization and full activation of the Hsp90 dimer in the closed conformation.

    “Ultimately, these changes lead to the N-terminal dimerization and full activation of the Hsp90 dimer in the closed conformation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The reduced spectral changes may indicate weaker binding to the switch region and thus explain the attenuated allosteric closing of the Hsp90 dimer.

    “However, the reduced spectral changes may also indicate weaker binding to this switch region and thus explain the attenuated allosteric closing of the Hsp90 dimer.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mutations in the Cα2 element or its surroundings impair GR activation in vitro and in vivo.

    “This is consistent with the fact that mutations in this element or its surroundings have been shown to impair GR activation in vitro and in vivo (2, 60, 62).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] D. F. Nathan, M. H. Vos, S. Lindquist, In vivo functions of the Saccharomyces cerevisiae Hsp90 chaperone. Proc. Natl. Acad. Sci. U.S.A. 94, 12949– 12956 (1997). 9371781 PMC24244 source

      Not checked in the free run.

    • cites [60] S. P. Bohen, K. R. Yamamoto, Isolation of Hsp90 mutants by screening for decreased steroid receptor function. Proc. Natl. Acad. Sci. U.S.A. 90, 11424– 11428 (1993). 8248264 PMC47995 source

      Not checked in the free run.

    • cites [62] O. Genest, M. Reidy, T. O. Street, J. R. Hoskins, J. L. Camberg, D. A. Agard, D. C. Masison, S. Wickner, Uncovering a region of heat shock protein 90 important for client binding in E. coli and chaperone function in yeast. Mol. Cell 49, 464– 473 (2013). 23260660 PMC3570620 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This explains the higher affinity for the ATP state and the inhibition of ATPase activity observed for the GR-LBD.

    “This explains the higher affinity for the ATP state and the inhibition of the ATPase activity observed for the GR-LBD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    In the open conformation of Hsp90, the ATP lid points toward client binding sites in the MD and CTD and forms a continuous binding surface.

    “In the open conformation of Hsp90, this element points toward the client binding sites in the MD and the CTD and forms a continuous binding surface.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The principle of conformational selection extends to p23, which selects the rotated conformation of the NTD in the presence of clients, promoting dimer closure and allosteric changes on the client binding site.

    “The principle of conformational selection also extends to the co-chaperone p23, which selects the rotated conformation of the NTD in the presence of clients, thus promoting dimer closure and allosteric changes on the client binding site.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Assignments of full-length yeast Hsp90 were supported by comparison with the NTD-MD construct and complemented by mutagenesis of several residues in the full-length protein lacking NOE networks.

    “Assignments were supported by comparison with the NTD-MD construct and complemented by mutagenesis of several residues in the full-length protein lacking NOE networks, namely, M16L, M105L, M116L, M382L, M389L, M589I, M593I, M603I, and M607I in the absence and presence of AMP-PNP.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Methyl groups in full-length human Hsp90 were assigned by transferring the assignment from the isolated domain and were validated using 3D CCH NOESY experiments.

    “Methyl groups in full-length Hsp90 were assigned by transferring the assignment from the isolated domain and were validated using 3D CCH NOESY experiments.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Hsp90 uses extensive "modular" binding sites for client interaction, where their availability and accessibility is modulated by conformational dynamics, nucleotides, and co-chaperones.

    “Our studies define Hsp90 as a molecular chaperone that uses extensive “modular” binding sites for client interaction, where their availability and accessibility is modulated by conformational dynamics, nucleotides, and co-chaperones.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Labeling of GR-LBD, MR-LBD, Tau, and p53-DBD does not change the activity of the proteins.

    “Labeling does not change the activity of the proteins as reported before (4, 16, 46).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] P. Sahasrabudhe, J. Rohrberg, M. M. Biebl, D. A. Rutz, J. Buchner, The plasticity of the Hsp90 Co-chaperone system. Mol. Cell 67, 947– 961.e5 (2017). 28890336 source

      Not checked in the free run.

    • cites [16] O. R. Lorenz, L. Freiburger, D. A. Rutz, M. Krause, B. K. Zierer, S. Alvira, J. Cuellar, J. M. Valpuesta, T. Madl, M. Sattler, J. Buchner, Modulation of the Hsp90 chaperone cycle by a stringent client protein. Mol. Cell 53, 941– 953 (2014). 24613341 source

      Not checked in the free run.

    • cites [46] V. Dahiya, G. Agam, J. Lawatscheck, D. A. Rutz, D. C. Lamb, J. Buchner, Coordinated conformational processing of the tumor suppressor protein p53 by the Hsp70 and Hsp90 chaperone machineries. Mol. Cell 74, 816– 830.e7 (2019). 31027879

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Background ATPase activity due to contaminations was subtracted from total activity by adding 50 μM radicicol to each reaction to obtain Hsp90-specific activity.

    “Background ATPase activity due to any contaminations was subtracted from the total activity by the addition of 50 μM Hsp90 inhibitor radicicol to each of the reaction to get Hsp90-specific activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The presence of multiple client binding motifs in Hsp90 seems required to handle the large number of clients processed by Hsp90 and suggests that conformational dynamics of both partners plays a major role in molecular recognition.

    “The presence of multiple client binding motifs in Hsp90 seems required to handle the large number of clients that are processed by Hsp90 and suggests that conformational dynamics of both partners plays a major role in molecular recognition.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For q calibration in SAXS, a silver behenate sample was used.

    “For q calibration, a silver behenate sample (Alfa Aesar) was used.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The ATP lid binds to clients in a conformation-sensitive manner, interacting with them only in the open conformation, while being displaced upon dimer closing or by p23.

    “Therefore, we propose that the ATP lid binds to clients in a conformation-sensitive manner, interacting with them only in the open conformation, while being displaced upon dimer closing or by p23.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    ATP-induced allostery enables communication between different domains of Hsp90, which can be fine-tuned and further modulated by co-chaperones such as p23, to adapt the Hsp90 conformational cycle in a client-specific manner.

    “ATP-induced allostery enables communication between different domains of Hsp90, which can be fine-tuned and further modulated by co-chaperones such as p23, to adapt the Hsp90 conformational cycle in a client-specific manner.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The individual domain assignment for human Hsp90 was further validated on the basis of the structure of the domains and their 3D CCH NOESY spectra.

    “The individual domain assignment was further validated on the basis of the structure of the domains and their 3D CCH NOESY spectra.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Isoform D of Tau contains the regions involved in Hsp90 interaction, and its binding to yeast Hsp90 was confirmed by NMR experiments of 15N-labeled Tau.

    “Isoform D of Tau, lacking the N-terminal negatively charged insert comprised between residues 45 and 102 of isoform F, contains the regions involved in Hsp90 interaction, and its binding to yeast Hsp90 was confirmed by NMR experiments of 15N-labeled Tau.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    SAXS samples were checked for beam damage.

    “Samples were measured in eight 900-s frames checked for beam damage, circular averaged, solvent-subtracted, and normalized to concentration by the SAXSLab software (version 3.1.1).”
    Quote in the paperNot a substantial claim
72 of 72

  • The paper relies on this without support.

    Hsp90 is a dimeric protein composed of three domains (NTD, MD, CTD) with the specified residue ranges.

    “Hsp90 is a dimeric protein composed of three domains.”

  • The paper relies on this without support.

    The underlying structural mechanisms by which clients modulate the Hsp90 conformational ensemble are poorly characterized.

    “However, the underlying structural mechanisms are poorly characterized.”

  • The paper relies on this without support.

    The limited availability of chemical shift assignments for full-length Hsp90 has so far precluded a comprehensive description of client interactions and conformational dynamics of Hsp90.

    “However, the limited availability of chemical shift assignments for full-length Hsp90 has, so far, precluded a comprehensive description of client interactions and conformational dynamics of Hsp90.”

  • The paper relies on this without support.

    The principles underlying the ATP-dependent dynamic conformational cycle of Hsp90 and its coupling to the recognition and processing of clients remain poorly understood.

    “In spite of recent advances, the principles underlying the ATP-dependent dynamic conformational cycle of Hsp90 and its coupling to the recognition and processing of clients remain poorly understood.”

  • The authors state this as an assumption.

    Crystal structures of Hsp90 proteins represent static low-energy states that may exist within the dynamic conformational ensemble of the Hsp90 dimer in solution.

    “Crystal structures of Hsp90 proteins are expected to represent static low-energy states (Fig. 1, A and B) that may exist within the dynamic conformational ensemble of the Hsp90 dimer in solution.”

  • The paper relies on this without support.

    p23 consists of a globular CS domain and a largely disordered charged C-terminal tail.

    “p23 consists of a globular CS (CHORD and Sgt1) domain and a largely disordered charged C-terminal tail.”

  • The paper relies on this without support.

    p53-DBD and Tau are characterized by low thermodynamic stability and/or aggregation propensity.

    “The p53-DBD and Tau are characterized by low thermodynamic stability and/or aggregation propensity.”

  • The paper relies on this without support.

    p23 supports the activation of GR and MR.

    “as p23 is known to support the activation of GR and MR.”
8 of 8

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?

  • AlphaFold, which predicts single ranked structures for a protein sequence, is unable to address directly allosteric mechanisms, which are based on populations of conformational states in ensembles.

    “AlphaFold, which predicts single ranked structures for a protein sequence, is unable to address directly allosteric mechanisms, which are based on the populations of conformational states in the ensembles.”

    From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [110]

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.

  • GR and MR hydrophobicity ranking reverses

    Major

    The results describe exposed hydrophobicity as increasing from GR to MR, whereas the discussion says GR has higher exposure than MR.

  • Two different radii are reported for ATP-bound Hsp90

    Major

    The results give radii of gyration of 57.6 Å and 61.3 Å for Hsp90-ATP without explaining the difference between those reported values.

  • Identical dissociation constants yield different theoretical complex fractions

    Minor

    Table 1 reports the same KD of 5.3 μM for these two entries, but gives different theoretical complex fractions under the stated standard conditions.

3 of 3

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Authors
Lopez, A., Dahiya, V., Delhommel, F., Freiburger, L., Stehle, R., Asami, S., Rutz, D., Blair, L., Buchner, J., & Sattler, M.
Affiliations
  • Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
  • Technical University of Munich (DE)
  • Helmholtz Munich (DE)
  • University of South Florida (US)
  • Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
Corresponding author
Sattler, Michael
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2021-12-17
Volume
7
Issue
51
Pages
eabl7295-eabl7295
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.abl7295
PMC
PMC8682993
OpenAlex
W4200441818
Semantic Scholar
d6187d53b1971fde2c7faa42437caf64106f8400
Cited by
59
References
94
Citations by year
2026: 14 · 2025: 9 · 2024: 17 · 2023: 9 · 2022: 10
FWCI
2.83
Type
journal article
Language
en
Open access
Locations
  • Science Advances (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • Site cant be reached (submittedVersion, cc-by-nc)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
Funders
National Institute on Aging (RF1AG055088)
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, molecular chaperones, allosteric communication, ATP binding, open and closed states, steroid hormone receptors, glucocorticoid receptor, mineralocorticoid receptor, p53, tau protein

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 by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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.

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