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Hsp90-Tau Complex Reveals Molecular Basis for Specificity in Chaperone Action
Open accessAbstract
Protein folding in the cell relies on the orchestrated action of conserved families of molecular chaperones, the Hsp70 and Hsp90 systems. Hsp70 acts early and Hsp90 late in the folding path, yet the molecular basis of this timing is enigmatic, mainly because the substrate specificity of Hsp90 is poorly understood. Here, we obtained a structural model of Hsp90 in complex with its natural disease-associated substrate, the intrinsically disordered Tau protein. Hsp90 binds to a broad region in Tau that includes the aggregation-prone repeats. Complementarily, a 106-Å-long substrate-binding interface in Hsp90 enables many low-affinity contacts. This allows recognition of scattered hydrophobic residues in late folding intermediates that remain after early burial of the Hsp70 sites. Our model resolves the paradox of how Hsp90 specifically selects for late folding intermediates but also for some intrinsically disordered proteins-through the eyes of Hsp90 they look the same.
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“By NMR, Hsp90 is identified to interact with tau transiently in the apo state and function as a scaffold in complex with FKBP51”
From The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state (2021) · cites this paper as Karagoz et al., 2014
Experimental — accuracy not yet measuredIn the citing paper
“In the absence of nucleotides, all clients show similar affinities in the low micromolar range for Hsp90 (Table 1), consistent with previous studies (16, 20, 48).”
From Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network (2021) · cites this paper as [48]
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“Tau physically interacts with Hsp90, and indeed provided the first 3D structure of a client complexed with Hsp90 (Karagöz et al., 2014).”
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“The middle domain (M-domain) is involved in client binding (7, 8), and the N-terminal domain binds ATP.”
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“The partial client mimetic:GRP94 interaction we have observed differs from chaperonesubstrate complexes seen in previously described complexes between Hsp90β and tau (Karagoz et al., 2014) and yeast Hsp90 and the glucocorticoid receptor ligand binding domain (GRlbd) (Lorenz et al.”
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Lupo, F., Tibaldi, E. V., Mattè, A., Sharma, A. K., Brunati, A. M., Alper, S. L., Zancanaro, C., Benati, D., Siciliano, A., Bertoldi, M., et al. (2016) · Blood · doi:10.1182/blood-2016-07-727321 · Cited by 70
“and autophagosomes that recognizes damaged proteins.(65,66) As shown inFigure 7A, chorea-acanthocytosis erythroblasts accumulated LAMP1 and p62 to higher levels than did healthy cells, consistent with impaired autophagy.”
BackgroundThe Unfolded Protein Response as a Guardian of the Secretory Pathway
Radanović, T., & Ernst, R. (2021) · Cells · doi:10.3390/cells10112965 · Cited by 77
“Whereas IRE1α’s affinity for such peptides is comparable to the range of affinities reported between molecular chaperones and their clients [112,113], it is notable that the peptide binding preference of human IRE1α and BiP are distinct [99].”
Hsp40s play complementary roles in the prevention of tau amyloid formation
Irwin, R., Faust, O., Petrovic, I. M., Wolf, S. G., Hofmann, H., & Rosenzweig, R. (2021) · eLife · doi:10.7554/elife.69601 · Cited by 66
Sinnige, T., Yu, A., & Morimoto, R. I. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-40204-4_4 · Cited by 65
Molecular mechanisms of amyloid formation in living systems
Sinnige, T. (2022) · Chemical Science · doi:10.1039/d2sc01278b · Cited by 67
Visualizing chaperone-assisted protein folding
Horowitz, S. A., Salmon, L., Koldewey, P., Ahlstrom, L. S., Martin, R., Quan, S., Afonine, P. V., van den Bedem, H., Wang, L., Xu, Q., et al. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3237 · Cited by 62
Wang, M., Shen, A., Zhang, C., Song, Z., Ai, J., Liu, H., Sun, L., Ding, J., Geng, M., & Zhang, A. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01106 · Cited by 62
Non-chaperone Proteins Can Inhibit Aggregation and Cytotoxicity of Alzheimer Amyloid β Peptide
Luo, J., Wärmländer, S. K. T. S., Gräslund, A., & Abrahams, J. P. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.574947 · Cited by 60
Cellular factors modulating the mechanism of tau protein aggregation
Fontaine, S. N., Sabbagh, J. J., Baker, J. D., Licha, C. R. M., Darling, A. L., & Dickey, C. A. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1839-9 · Cited by 66
Self-citationZhuravleva, A., & Korzhnev, D. M. (2016) · Progress in Nuclear Magnetic Resonance Spectroscopy · doi:10.1016/j.pnmrs.2016.10.002 · Cited by 60
Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network
Lopez, A., Dahiya, V., Delhommel, F., Freiburger, L., Stehle, R., Asami, S., Rutz, D., Blair, L., Buchner, J., & Sattler, M. (2021) · Science Advances · doi:10.1126/sciadv.abl7295 · Cited by 59
Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau
Ferrari, L., Stucchi, R., Konstantoulea, K., van de Kamp, G., Kos, R., Geerts, W. J. C., van Bezouwen, L. S., Förster, F. G., Altelaar, M. A. F., Hoogenraad, C. C., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13745-7 · Cited by 65
Self-citationMechanistic basis for the recognition of a misfolded protein by the molecular chaperone Hsp90
Oroz, J., Kim, J. H., Chang, B. J., & Zweckstetter, M. (2017) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3380 · Cited by 58
Self-citationHsp multichaperone complex buffers pathologically modified Tau
Moll, A., Ramirez, L. M., Ninov, M., Schwarz, J., Urlaub, H., & Zweckstetter, M. (2022) · Nature Communications · doi:10.1038/s41467-022-31396-z · Cited by 60
Self-citationThe Hsp90 molecular chaperone governs client proteins by targeting intrinsically disordered regions
Kolhe, J. A., Babu, N. L., & Freeman, B. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.05.021 · Cited by 59
Chaperone-Bound Clients: The Importance of Being Dynamic
Hiller, S. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2018.12.005 · Cited by 54
“Just as for the Skp–Omp complex, this model underscores the importance of multiple non-specific low-affinity contacts to build up towards a global high affinity interaction by avidity (28).”
BackgroundYu, A., Fox, S. G., Cavallini, A., Kerridge, C., O’Neill, M. J., Wolak, J., Bose, S., & Morimoto, R. I. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.007527 · Cited by 55
“isoforms can interact with a subset of the chaperone network to assist proper folding and prevent misfolding and aggregation (50,52-54).”
BackgroundHsp70-mediated quality control: should I stay or should I go?
Kohler, V., & Andréasson, C. (2020) · Biological Chemistry · doi:10.1515/hsz-2020-0187 · Cited by 59
Drepper, F., Biernat, J., Kaniyappan, S., Meyer, H. E., Mandelkow, E., Warscheid, B., & Mandelkow�, E. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.015882 · Cited by 56
“Finally, there are numerous examples of interactions between Tau and chaperones (81), a class that is prominent among the identified associated proteins.”
BackgroundSelf-citationDnaJC7 binds natively folded structural elements in tau to inhibit amyloid formation
Hou, Z., Wydorski, P. M., Perez, V. A., Mendoza‐Oliva, A., Ryder, B. D., Mirbaha, H., Kashmer, O. M., & Joachimiak, Ł. A. (2021) · Nature Communications · doi:10.1038/s41467-021-25635-y · Cited by 53
How do protein aggregates escape quality control in neurodegeneration?
Koopman, M. B., Ferrari, L., & Rüdiger, S. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.01.006 · Cited by 54
Self-citationHsp90: From Cellular to Organismal Proteostasis
Somogyvári, M., Khatatneh, S., & Sőti, C. (2022) · Cells · doi:10.3390/cells11162479 · Cited by 55
“Some clients bind to Hsp90 with a moderate affinity [42,50,51], while for other clients, the affinity is affected by Hsp90 conformation, as in the case of glucocorticoid receptors (GR).”
BackgroundProteomic analysis of protein homeostasis and aggregation
Laskowska, E., Kuczyńska‐Wiśnik, D., & Lipińska, B. (2018) · Journal of Proteomics · doi:10.1016/j.jprot.2018.12.003 · Cited by 49
Folding while bound to chaperones
Horowitz, S. A., Koldewey, P., Stull, F. W., & Bardwell, J. C. A. (2017) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2017.06.009 · Cited by 48
He, W.-T., Xue, W., Gao, Y., Hong, J.-Y., Yue, H.-W., Jiang, L.-L., & Hu, H.-Y. (2017) · Scientific Reports · doi:10.1038/s41598-017-13711-7 · Cited by 46
Advances towards Understanding the Mechanism of Action of the Hsp90 Complex
Prodromou, C., & Bjorklund, D. M. (2022) · Biomolecules · doi:10.3390/biom12050600 · Cited by 48
“Using an NMR approach, together with small angle scattering, a structural model was obtained for the interaction between Hsp90 and Tau [77].”
BackgroundMethodInfluentialCo-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome
Abildgaard, A. B., Gersing, S. K., Larsen-Ledet, S., Nielsen, S. V., Stein, A., Lindorff‐Larsen, K., & Hartmann‐Petersen, R. (2020) · Biomolecules · doi:10.3390/biom10081141 · Cited by 45
“This client preference is facilitated by the large substrate-binding interface of HSP90 [118].”
BackgroundPremji, T. P., Dash, B. S., Das, S., & Chen, J. (2024) · Nanomaterials · doi:10.3390/nano14010112 · Cited by 47
Cesa, L. C., Shao, H., Srinivasan, S. R., Tse, E., Jain, C., Zuiderweg, E. R. P., Southworth, D. R., Mapp, A. K., & Gestwicki, J. E. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.000634 · Cited by 44
“Hsp90 has been reported to bind a more restricted set of ~200 kinases and transcription factors (5), but it also binds to some intrinsically disordered proteins, including tau (31,32).”
BackgroundMethodAndo, K., Oka, M., Ohtake, Y., Motoki, H., Shimizu, S., Hisanaga, S., & Iijima, K. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.08.053 · Cited by 40
Chaperones and chaperone–substrate complexes: Dynamic playgrounds for NMR spectroscopists
Burmann, B. M., & Hiller, S. (2015) · Progress in Nuclear Magnetic Resonance Spectroscopy · doi:10.1016/j.pnmrs.2015.02.004 · Cited by 40
“Chemical shift perturbation [102, 180, 181, 188, 189, 191, 192, 194, 204] [211, 216-219, 222] [84, 277] [91] [260, 266] [313, 314] [88, 123, 146, 151-154, 162] [233, 235] [48] [236, 244, 245, 248-250, 253]”
BackgroundResultInfluentialChaperoning shape-shifting tau in disease
Ryder, B. D., Wydorski, P. M., Hou, Z., & Joachimiak, Ł. A. (2022) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2021.12.009 · Cited by 44
Metamorphism in TDP-43 prion-like domain determines chaperone recognition
Carrasco, J., Antón, R., Valbuena, A., Pantoja‐Uceda, D., Mukhi, M., Hervás, R., Laurents, D. V., Gasset, M., & Oroz, J. (2023) · Nature Communications · doi:10.1038/s41467-023-36023-z · Cited by 39
Lorenzo, D. D. (2024) · ChemMedChem · doi:10.1002/cmdc.202400180 · Cited by 46
Targeting the mitochondrial chaperone TRAP1: strategies and therapeutic perspectives
Serapian, S. A., Sànchez‐Martìn, C., Moroni, E., Rasola, A., & Colombo, G. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.04.003 · Cited by 39
Metadata
- Authors
- Karagöz, G. E., Duarte, A. M. S., Akoury, E., Ippel, H., Biernat, J., Morán Luengo, T., Radli, M., Didenko, T., Nordhues, B. A., Veprintsev, D. B., Dickey, C. A., Mandelkow, E., Zweckstetter, M., Boelens, R., Madl, T., & Rüdiger, S. G. D.
- Affiliations
- Howard Hughes Medical Institute (US)
- Utrecht University (NL)
- Max Planck Institute for Biophysical Chemistry (DE)
- German Center for Neurodegenerative Diseases (DE)
- University of South Florida (US)
- Paul Scherrer Institute (CH)
- University of Graz (AT)
- Corresponding author
- Madl, Tobias
- Rüdiger, Stefan G.D.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 156
- Issue
- 5
- Pages
- 963-974
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4263503
- OpenAlex
- W1993050837
- Cited by
- 318
- References
- 68
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 22 · 2023: 31 · 2022: 27 · 2021: 19 · 2020: 27 · 2019: 33 · 2018: 32 · 2017: 31 · 2016: 26 · 2015: 26 · 2014: 10
- FWCI
- 12.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Max Planck Digital Library (submittedVersion, other-oa)
- Max Planck Digital Library (submittedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Site cant be reached (submittedVersion)
- DZNE Pub (submittedVersion)
- GRO (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- European Commission (261863)
- National Institute of Neurological Disorders and Stroke (R01NS073899, NS073899)
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- HSP90, tau protein, molecular chaperones, protein folding, substrate specificity, intrinsically disordered proteins, HSP70, folding intermediates, hydrophobic residues
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Humans, Models, Molecular, Molecular Sequence Data, X-Ray Diffraction, tau Proteins, Protein Folding, HSP90 Heat-Shock Proteins, Scattering, Small Angle
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