The Co-chaperone p23 Arrests the Hsp90 ATPase Cycle to Trap Client Proteins
Abstract
The action of the molecular chaperone Hsp90 is essential for the activation and assembly of an increasing number of client proteins. This function of Hsp90 has been proposed to be governed by conformational changes driven by ATP binding and hydrolysis. Association of co-chaperones and client proteins regulate the ATPase activity of Hsp90. Here, we have examined the inhibition of the ATPase activity of human Hsp90beta by one such co-chaperone, human p23. We demonstrate that human p23 interacts with Hsp90 in both the absence and presence of nucleotide with a higher affinity in the presence of the ATP analogue AMP-PNP. This is consistent with an analysis of the effect of p23 on the steady-state kinetics that revealed a mixed mechanism of inhibition. Mass spectrometry of the intact Hsp90.p23 complex determined the stoichiometry of binding to be one p23 to each subunit of the Hsp90 dimer. p23 was also shown to interact with a monomeric, truncated fragment of Hsp90, lacking the C-terminal homodimerisation domain, indicating dimerisation of Hsp90 is not a prerequisite for association with p23. Complex formation between Hsp90 and p23 increased the apparent affinity of Hsp90 for AMP-PNP and completely inhibited the ATPase activity. We propose a model where the role of p23 is to lock individual subunits of Hsp90 in an ATP-dependent conformational state that has a high affinity for client proteins.
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p23 binds directly to the ATP form of Hsp90, and this stabilizes Hsp90-client protein interactions.
“because the cochaperone p23 binds directly to the ATP form of Hsp90, and this stabilizes Hsp90-client protein interactions (1, 14, 15).”
From FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells (2010) · cites this paper as [14]
p23 selectively binds to the ATP form of Hsp90, stabilizes the closed state, and promotes Hsp90 interactions with client proteins.
“Through selective binding to the ATP form of Hsp90, p23 stabilizes the 'closed' state and promotes Hsp90 interactions with client proteins (14, 33).”
From FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells (2010) · cites this paper as [14]
p23 is a cochaperone known to stabilize Hsp90 binding to client proteins.
“a cochaperone known to stabilize Hsp90 binding to client proteins (14)”
From FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells (2010) · cites this paper as [14]
Cites
Meyer, P., Prodromou, C., Hu, B., Vaughan, C., Roe, S. M., Panaretou, B., Piper, P. W., & Pearl, L. H. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00065-0 · Cited by 491 · see citing works
Freeman, B. C., Toft, D. O., & Morimoto, R. I. (1996) · Science · doi:10.1126/science.274.5293.1718 · Cited by 370 · see citing works
Co-chaperone regulation of conformational switching in the Hsp90 ATPase cycle
Siligardi, G., Hu, B., Panaretou, B., Piper, P. W., Pearl, L. H., & Prodromou, C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410562200 · Cited by 207 · cited 6× · see citing works
“In sharp contrast to human p23, Sba1 inhibits the ATPase activity of yeast Hsp90 only partially.(33,34) The level of sequence identity is 27% in the globular cores of human and yeast p23 compared to 64% identity for the respective Hsp90 homologues.”
BackgroundMethodResultInfluentialMillson, S. H., Truman, A. W., King, V., Prodromou, C., Pearl, L. H., & Piper, P. W. (2005) · Eukaryotic Cell · doi:10.1128/ec.4.5.849-860.2005 · Cited by 172 · see citing works
Freeman, B. C., Felts, S. J., Toft, D. O., & Yamamoto, K. R. (2000) · Genes & Development · doi:10.1101/gad.14.4.422 · Cited by 168 · cited 1× · see citing works
“Opposing a role in assisting the assembly process, p23 may alter the transcriptional activity of nuclear receptors by affecting the dissociation rate of the receptor–DNA response element complex.(28) The molecular mechanism by which p23 acts as a co-chaperone for Hsp90 is unknown.”
BackgroundRichter, K., Walter, S., & Buchner, J. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.07.064 · Cited by 159 · cited 12× · see citing works
“In sharp contrast to human p23, Sba1 inhibits the ATPase activity of yeast Hsp90 only partially.(33,34) The level of sequence identity is 27% in the globular cores of human and yeast p23 compared to 64% identity for the respective Hsp90 homologues.”
BackgroundMethodResultInfluentialRole for Hsp90-Associated Cochaperone p23 in Estrogen Receptor Signal Transduction
Knoblauch, R., & Garabedian, M. J. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.5.3748 · Cited by 126 · see citing works
The Influence of ATP and p23 on the Conformation of hsp90
Sullivan, W. P., Owen, B. A. L., & Toft, D. O. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207754200 · Cited by 111 · see citing works
Bohen, S. P. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.6.3330 · Cited by 106 · see citing works
Weikl, T., Abelmann, K., & Buchner, J. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3172 · Cited by 97 · cited 1× · see citing works
“ent dimeric molecular mass calculated from sizeexclusion chromatography is most likely due to the unstructured C-terminal acidic tail of p23 increasing the apparent diameter of p23.(41) This would give rise to an aberrant elution profile during sizeexclusion chromatography, as observed.”
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Sorted by citations
HSP90 at the hub of protein homeostasis: emerging mechanistic insights
Taipale, M., Jarosz, D. F., & Lindquist, S. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2918 · Cited by 1,818 · see citing works
“This high degree of conformational flexibility could certainly be regulated in cells by the interaction with clients and co-chaperone”
BackgroundStructure, Function, and Regulation of the Hsp90 MachineryPreprint
Biebl, M. M., & Büchner, J. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a034017 · Cited by 308 · see citing works
“The general model of the Hsp90 ATPase cycle is applicable to all Hsp90 paralogs and isoforms.”
BackgroundInfluentialThe Hsp90 chaperone machinery: Conformational dynamics and regulation by co-chaperones
Li, J., Soroka, J., & Buchner, J. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.09.003 · Cited by 498 · see citing works
The Hsp90 molecular chaperone: an open and shut case for treatment
Pearl, L. H., Prodromou, C., & Workman, P. (2008) · Biochemical Journal · doi:10.1042/bj20071640 · Cited by 447 · see citing works
The role of mass spectrometry in structure elucidation of dynamic protein complexes.
Sharon, M., & Robinson, C. (2007) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.76.061005.090816 · Cited by 364 · see citing works
Self-citationThe Therapeutic Target Hsp90 and Cancer Hallmarks
Miyata, Y., Nakamoto, H., & Neckers, L. (2012) · Current pharmaceutical design · doi:10.2174/138161213804143725 · Cited by 335 · see citing works
“chaperones and client proteins that stimulate hydrolysis or by dissociation of p23 from Hsp90 [34, 64].”
BackgroundJackson, S. (2012) · Topics in current chemistry · doi:10.1007/128_2012_356 · Cited by 334 · see citing works
“Although there is some evidence from mass spectrometric analysis that complexes of one p23 bound to the Hsp90 dimer can exist [165], other studies have shown that two molecules of p23 bind to the dimer [164], and this is indeed clearly the case in the crystal structure [71] (Fig.”
BackgroundSelf-citationConformational dynamics of the molecular chaperone Hsp90
Krukenberg, K. A., Street, T. O., Lavery, L. A., & Agard, D. A. (2011) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583510000314 · Cited by 308 · see citing works
“The complex promotes and stabilizes a catalytically incompetent closed conformation (McLaughlin et al. 2002, 2006 ; Richter et al. 2004 ; Siligardi et al. 2004).”
BackgroundEvolution and function of diverse Hsp90 homologs and cochaperone proteins
Johnson, J. L. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.09.020 · Cited by 283 · see citing works
Post-translational modifications of Hsp90 and their contributions to chaperone regulation
Mollapour, M., & Neckers, L. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.07.018 · Cited by 288 · see citing works
The chaperone Hsp90: changing partners for demanding clients
Röhl, A., Rohrberg, J., & Büchner, J. (2013) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2013.02.003 · Cited by 268 · see citing works
Mechanisms of Hsp90 regulation
Prodromou, C. (2016) · Biochemical Journal · doi:10.1042/bcj20160005 · Cited by 310 · see citing works
Survey of the year 2003 commercial optical biosensor literature
Rich, R. L., & Myszka, D. G. (2004) · Journal of Molecular Recognition · doi:10.1002/jmr.726 · Cited by 505 · see citing works
Asymmetric Activation of the Hsp90 Dimer by Its Cochaperone Aha1
Retzlaff, M., Hagn, F., Mitschke, L., Heßling, M., Gugel, F., Kessler, H., Richter, K., & Büchner, J. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.01.006 · Cited by 244 · see citing works
“Our results on the presence of an activating and inhibiting chaperone suggest that ternary complexes are possible and that, in these, the activator Aha1 and either Hop/Sti1 or p23/Sba1 could act on Hsp90 at the same time.”
BackgroundInfluentialSouthworth, D., & Agard, D. (2008) · Molecules and Cells · doi:10.1016/j.molcel.2008.10.024 · Cited by 225 · see citing works
“This interaction is known to significantly slow the hydrolysis rate and stabilize client-bound Hsp90 complexes (McLaughlin et al., 2006).”
BackgroundFirefly luciferase mutants as sensors of proteome stress
Gupta, R., Kasturi, P., Bracher, A., Loew, C., Zheng, M., Villella, A., Garza, D., Hartl, F. U., & Raychaudhuri, S. (2011) · Nature Methods · doi:10.1038/nmeth.1697 · Cited by 219 · see citing works
Li, Z.-L., Song, F., Zhuang, Z., Dunaway-Mariano, D., & Anderson, K. S. (2009) · Analytical Biochemistry · doi:10.1016/j.ab.2009.07.030 · Cited by 212
Rao, R., Fiskus, W. C., Yang, Y., Lee, P., Joshi, R., Fernandez, P., Mandawat, A., Atadja, P. W., Bradner, J. E., & Bhalla, K. N. (2008) · Blood · doi:10.1182/blood-2008-03-143644 · Cited by 189 · see citing works
Swe1Wee1-Dependent Tyrosine Phosphorylation of Hsp90 Regulates Distinct Facets of Chaperone Function
Mollapour, M., Tsutsumi, S., Donnelly, A. C., Beebe, K., Tokita, M. J., Lee, M.-J., Lee, S., Morra, G., Bourboulia, D., Scroggins, B. T., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.01.005 · Cited by 196 · see citing works
“, 2008), and p23 (McLaughlin et al., 2006; Picard, 2006) inhibit the Hsp90 ATPase cycle, while Aha1 (Panaretou et al.”
The role of Hsp90 in protein complex assembly
Makhnevych, T., & Houry, W. A. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.09.001 · Cited by 184 · see citing works
“For example, cochaperones regulate Hsp90 by modulating its rate of ATP hydrolysis (Aha1, Cdc37, p23), conformational flexibility (p23, Sgt1), and the binding of specific substrates or higher-order protein complex assembly (HOP, Cdc37, Sgt1) [24–29].”
BackgroundHSP90AB1: Helping the good and the bad
Haase, M., & Fitze, G. (2016) · Gene · doi:10.1016/j.gene.2015.08.063 · Cited by 179 · see citing works
“HSP90 converts to a closed conformation after binding of ATP and binding of p23 (Johnson et al. 1994; Johnson & Toft 1995; Freeman et al. 2000; McLaughlin et al. 2006; Forafonov et al. 2008), releasing Hop and HSC70 from the complex, leaving space for another PPIase molecule.”
BackgroundThe ‘active life’ of Hsp90 complexes
Prodromou, C. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.07.020 · Cited by 171 · see citing works
“A more robust inhibition was, however, seen with p23, the human homolog of Sba1 [47].”
BackgroundInfluentialStructural and functional complexity of HSP90 in cellular homeostasis and disease
Chiosis, G., Digwal, C. S., Trepel, J., & Neckers, L. (2023) · Nature reviews. Molecular cell biology · doi:10.1038/s41580-023-00640-9 · Cited by 174 · see citing works
The Genomes of Three Uneven Siblings: Footprints of the Lifestyles of Three Trichoderma Species
Schmoll, M., Dattenböck, C., Carreras-Villaseñor, N., Mendoza‐Mendoza, A., Tisch, D., Alemán-Duarte, M. I., Baker, S., Brown, C. M., Cervantes-Badillo, M. G., Cetz-Chel, J. E., et al. (2016) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00040-15 · Cited by 190 · see citing works
Survey of the year 2005: literature on applications of isothermal titration calorimetry
Ababou, A., & Ladbury, J. (2007) · Journal of Molecular Recognition · doi:10.1002/jmr.803 · Cited by 164 · see citing works
Ni, L., Yang, C.-S., Gioeli, D., Frierson, H., Toft, D. O., & Paschal, B. M. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01891-08 · Cited by 155 · see citing works
“This involves FKBP51 contact with Hsp90 and recruitment of p23, a cochaperone known to stabilize Hsp90 binding to client proteins (14).”
BackgroundLavery, L. A., Partridge, J. R., Ramelot, T. A., Elnatan, D., Kennedy, M. A., & Agard, D. A. (2014) · Molecular Cell · doi:10.1016/j.molcel.2013.12.023 · Cited by 158 · see citing works
“, 1995) and has been shown to inhibit Hsp90 ATPase activity (McLaughlin et al., 2006).”
BackgroundMixed Hsp90–cochaperone complexes are important for the progression of the reaction cycle
Li, J., Richter, K., & Buchner, J. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1965 · Cited by 155 · see citing works
“In addition to the Hop / Sti1 – Hsp90 complex, a second complex, which contains a PPIase and the cochaperone p23 (also called Sba1 in yeast), has been found to be part of the cycle at a later stag”
BackgroundThe Charged Linker Region Is an Important Regulator of Hsp90 Function*
Hainzl, O., Lapina, M. C., Buchner, J., & Richter, K. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.031658 · Cited by 150 · see citing works
Loss of HDAC6, a novel CHIP substrate, alleviates abnormal tau accumulation
Cook, C. N., Gendron, T. F., Scheffel, K., Carlomagno, Y., Dunmore, J. H., Deture, M. A., & Petrucelli, L. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds125 · Cited by 129 · see citing works
“The cochaperone p23 locks Hsp90 in a conformational state that has a high affinity for client proteins (31).”
BackgroundIntegration of the accelerator Aha1 in the Hsp90 co-chaperone cycle
Li, J., Richter, K., Reinstein, J., & Büchner, J. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2502 · Cited by 132 · see citing works
Dimerization of Hsp90 Is Required for in Vivo Function
Wayne, N., & Bolon, D. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m703844200 · Cited by 117 · see citing works
Heat Shock Proteins in Association with Heat Tolerance in Grasses
Xu, Y., Zhan, C., & Huang, B. (2011) · International Journal of Proteomics · doi:10.1155/2011/529648 · Cited by 113
Targeting Hsp90 and its co-chaperones to treat Alzheimer’s disease
Blair, L. J., Sabbagh, J. J., & Dickey, C. (2014) · Expert opinion on therapeutic targets · doi:10.1517/14728222.2014.943185 · Cited by 113 · see citing works
“p23 binds to Hsp90 simultaneously with other co-chaperones and can extend client-Hsp90 binding by regulating the length of time between ATP hydrolysis [91].”
BackgroundN-terminal domain of human Hsp90 triggers binding to the cochaperone p23
Karagöz, G. E., Duarte, A. M. S., Ippel, H., Uetrecht, C., Sinnige, T., van Rosmalen, M., Hausmann, J., Heck, A. J. R., Boelens, R., & Rüdiger, S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1011867108 · Cited by 124 · see citing works
“Our data are in agreement with earlier findings that the human Hsp90 dimer preferentially binds two p23 molecules (13, 35).”
ResultMorgner, N., Schmidt, C., Beilsten-Edmands, V., Ebong, I.-O., Patel, N. A., Clerico, E. M., Kirschke, E., Daturpalli, S., Jackson, S. E., Agard, D., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.03.063 · Cited by 106 · see citing works
“described (McLaughlin et al., 2006).”
MethodSelf-citationCunningham, C. N., Krukenberg, K., & Agard, D. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800046200 · Cited by 105 · see citing works
ATP‐driven molecular chaperone machines
Clare, D. K., & Saibil, H. R. (2013) · Biopolymers · doi:10.1002/bip.22361 · Cited by 100 · see citing works
Yin, S., Xie, Y., & Loo, J. (2008) · Journal of the American Society for Mass Spectrometry · doi:10.1016/j.jasms.2008.05.012 · Cited by 101 · see citing works
“Protein–nucleotide complexes have been detected using ESI-MS [14, 27–30].”
BackgroundMethodResultInfluentialCloutier, P., & Coulombe, B. (2013) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2013.02.010 · Cited by 94 · see citing works
Gano, J. J., & Simon, J. (2009) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m900261-mcp200 · Cited by 89 · see citing works
“These results are consistent with previous findings showing p23 and AHSA1 to have an increased binding affinity for HSP90 in its ATP-bound state (13, 40) and”
Resultp23/Sba1p protects against Hsp90 inhibitors independently of its intrinsic chaperone activity
Forafonov, F., Toogun, O. A., Grad, I., Suslova, E., Freeman, B. C., & Picard, D. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.02246-07 · Cited by 84 · see citing works
“5B), which is consistent with a stabilization of the ATP-bound form (9, 33, 52, 56).”
BackgroundHsp90: Friends, clients and natural foes
Verma, S., Goyal, S., Jamal, S., Singh, A. P., & Grover, A. (2016) · Biochimie · doi:10.1016/j.biochi.2016.05.018 · Cited by 90 · see citing works
Flom, G. A., Behal, R. H., Rosen, L., Cole, D. G., & Johnson, J. L. (2007) · Biochemical Journal · doi:10.1042/bj20070084 · Cited by 80 · see citing works
Hsp90 and Client Protein Maturation
Wayne, N., Mishra, P., & Bolon, D. N. A. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-295-3_3 · Cited by 83 · see citing works
Johnson, J. L., Halaś, A., & Flom, G. A. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.01034-06 · Cited by 76 · see citing works
“However, purified Sba1 inhibited the ATPase activity of purified Hsp82, although the effects were variable (18, 26, 32, 41).”
BackgroundStructure, Function and Regulation of the Hsp90 Machinery
Büchner, J., & Li, J. (2013) · Biomedical Journal · doi:10.4103/2319-4170.113230 · Cited by 421 · see citing works
“As a result, the ATP hydrolysis, which is indispensable for the release of the client protein, is partially inhibited in the presence of p23/Sba1.([41,62])”
Backgroundda Silva, V. C. H., & Ramos, C. H. I. (2012) · Journal of Proteomics · doi:10.1016/j.jprot.2011.12.028 · Cited by 76 · see citing works
“The p23 co-chaperone is involved in client maturation and binds to Hsp90s bound to ATP, inhibiting ATPase activity [38,55].”
BackgroundHsp90 structure and function studied by NMR spectroscopy
Didenko, T., Duarte, A. M. S., Karagöz, G. E., & Rüdiger, S. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.11.009 · Cited by 79 · see citing works
“In case of the Hsp90–p23 interaction NMR conditions at high ionic strength were in pleasing congruence with crystallographic and biochemical data [22,88].”
BackgroundResultInfluentialMass Spectrometry Methods for Measuring Protein Stability
Vallejo, D. D., Ramírez, C. R., Parson, K. F., Han, Y., Gadkari, V. V., & Ruotolo, B. T. (2022) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00857 · Cited by 82 · see citing works
The Mechanism of Hsp90 ATPase Stimulation by Aha1
Wolmarans, A., Lee, B., Spyracopoulos, L., & LaPointe, P. (2016) · Scientific Reports · doi:10.1038/srep33179 · Cited by 72 · see citing works
Characterisation of the Plasmodium falciparum Hsp70–Hsp90 organising protein (PfHop)
Gitau, G. W., Mandal, P., Blatch, G. L., Przyborski, J. M., & Shonhai, A. (2011) · Cell Stress and Chaperones · doi:10.1007/s12192-011-0299-x · Cited by 79 · see citing works
Localization of Sites of Interaction between p23 and Hsp90 in Solution*
Martinez-Yamout, M., Venkitakrishnan, R., Preece, N., Kroon, G., Wright, P., & Dyson, H. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601759200 · Cited by 65 · see citing works
Biebl, M. M., Lopez, A., Rehn, A., Freiburger, L., Lawatscheck, J., Blank, B., Sattler, M., & Buchner, J. (2021) · Nature Communications · doi:10.1038/s41467-021-21063-0 · Cited by 58 · see citing works
Molecular Cochaperones: Tumor Growth and Cancer Treatment
Calderwood, S. K. (2013) · Scientifica · doi:10.1155/2013/217513 · Cited by 63 · see citing works
“The mechanisms which underlie the elevated expression of molecular chaperones of the HSPA and HSPD families in cancer are currently unclear but may involve the dysregulation of transcription factor HSF1 first shown to couple stress to HSP transcription [8, 26].”
BackgroundInfluentialContributions of co-chaperones and post-translational modifications towards Hsp90 drug sensitivity
Walton-Diaz, A., Khan, S., Bourboulia, D., Trepel, J., Neckers, L., & Mollapour, M. (2013) · Future Medicinal Chemistry · doi:10.4155/fmc.13.88 · Cited by 58 · see citing works
Molecular Pathways: Targeting Hsp90—Who Benefits and Who Does Not
Scaltriti, M., Dawood, S. S., & Cortés, J. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2138 · Cited by 67 · see citing works
“ATP binds to Hsp90 dimers, forcing them to assume a “closed” conformation, which in turn facilitates the interaction with the co-chaperone p23, and the dissociation from Hop (22-25).”
A common conformationally coupled ATPase mechanism for yeast and human cytoplasmic HSP90s
Vaughan, C. K., Piper, P. W., Pearl, L. H., & Prodromou, C. (2008) · FEBS Journal · doi:10.1111/j.1742-4658.2008.06773.x · Cited by 56 · see citing works
Functional principles and regulation of molecular chaperones
Dahiya, V., & Büchner, J. (2018) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2018.10.001 · Cited by 75 · see citing works
Averna, M., Stifanese, R., Tullio, R. D., Passalacqua, M., Salamino, F., Pontremoli, S., & Melloni, E. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803638200 · Cited by 55
Dixit, A., & Verkhivker, G. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037605 · Cited by 53 · see citing works
Oxelmark, E., Roth, J., Brooks, P., Braunstein, S., Schneider, R., & Garabedian, M. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00009-06 · Cited by 53 · see citing works
“A recent biochemical study suggests that human p23 secures Hsp90 into an ATP-bound form, thus facilitating Hsp90 interaction with client proteins (25).”
BackgroundPost-translational modification of heat-shock protein 90: impact on chaperone function
Scroggins, B. T., & Neckers, L. (2007) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2.10.1403 · Cited by 52 · see citing works
Alternative approaches to Hsp90 modulation for the treatment of cancer
Hall, J. A., Forsberg, L. K., & Blagg, B. (2014) · Future Medicinal Chemistry · doi:10.4155/fmc.14.89 · Cited by 50 · see citing works
“p23 is a well-established regulator of Hsp90 ATPase activity and has been shown to inhibit ATP hydrolysis and client release [36,37].”
BackgroundPhillips, J., Yao, Z.-P., Zhang, W., McLaughlin, S., Laue, E., Robinson, C., & Jackson, S. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.04.059 · Cited by 50 · see citing works
Self-citationReebye, V., Querol Cano, L., Lavery, D. N., Brooke, G. N., Powell, S. M., Chotai, D., Walker, M. M., Whitaker, H. C., Wait, R., Hurst, H. C., et al. (2012) · Molecular Endocrinology · doi:10.1210/me.2012-1056 · Cited by 47 · see citing works
“(30), it could also be a target to reduce HSP90 activity within”
BackgroundMeng, Q., Chen, X., Sun, L., Zhao, C., Sui, G., & Cai, L. (2010) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-010-0651-y · Cited by 48 · see citing works
“According to McLaughlin [21], p23 binding to ATP-bound Hsp90 is essential to a stable ATP-dependent conformational state and high affinity for client proteins.”
BackgroundDean, M. E., & Johnson, J. L. (2020) · Cell Stress and Chaperones · doi:10.1007/s12192-020-01167-0 · Cited by 48 · see citing works
Ebong, I., Beilsten-Edmands, V., Patel, N., Morgner, N., & Robinson, C. (2016) · Cell Discovery · doi:10.1038/celldisc.2016.2 · Cited by 47 · see citing works
Self-citationAdvances towards Understanding the Mechanism of Action of the Hsp90 Complex
Prodromou, C., & Bjorklund, D. M. (2022) · Biomolecules · doi:10.3390/biom12050600 · Cited by 47 · see citing works
“This is not too dissimilar to the action of Aha1, although for Sba1/p23 the ATPase activity is downregulated [35,49].”
BackgroundCo-chaperone p23 Regulates C. elegans Lifespan in Response to Temperature
Horikawa, M., Sural, S., Hsu, A., & Antebi, A. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005023 · Cited by 44 · see citing works
“Interactions with HSP90 and cGMP signaling In its capacity as co-chaperone, p23 is known to complex with HSP90 [16–18,47].”
Lu, X., Wang, X., Zhuo, W., Jia, L., Jiang, Y., Fu, Y., & Luo, Y. (2013) · Biochemical Journal · doi:10.1042/bj20130963 · Cited by 42 · see citing works
“Previous reports have shown that this process is ATP-dependent [29] and can be stimulated by the co-chaperone p23 [30].”
BackgroundSTAT3 interacts directly with Hsp90
Prinsloo, E., Kramer, A. H., Edkins, A., & Blatch, G. L. (2012) · IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology · doi:10.1002/iub.607 · Cited by 43
ATP Binding to Hsp90 Is Sufficient for Effective Chaperoning of p53 Protein*
Walerych, D., Gutkowska, M., Klejman, M. P., Wawrzynów, B., Tracz, Z., Wiech, M., Żylicz, M., & Zylicz, A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.112110 · Cited by 43 · see citing works
Li, Y., Zhang, T., Schwartz, S. J., & Sun, D. (2011) · Nutrition and Cancer · doi:10.1080/01635581.2011.596645 · Cited by 37 · see citing works
“On the other hand, it was demonstrated that p23 is recruited to the ATP-bound, closed conformation of Hsp90 and locks it in an ATP-dependent conformational state that has high affinity for client proteins ( 54 ).”
BackgroundZhu, X.-J., Liu, X., Jin, Q., Cai, Y., Yang, Y., & Zhou, T. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.105494 · Cited by 39 · see citing works
Pare, J. M., LaPointe, P., & Hobman, T. C. (2013) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-12-0892 · Cited by 40 · see citing works
“(2006), increases “dwell time” and allows for successful client maturation (Dittmar et al., 1997; McLaughlin et al., 2006).”
BackgroundMutations that increase both Hsp90 ATPase activity in vitro and Hsp90 drug resistance in vivo.
Żurawska, A., Urbański, J., Matulienė, J., Baraniak, J., Klejman, M. P., Filipek, S., Matulis, D., & Bieganowski, P. (2010) · Biochimica et Biophysica Acta · doi:10.1016/j.bbamcr.2010.03.002 · Cited by 39 · see citing works
“Sba1 binds to the N-terminal domain of Hsp90 and decreases rate of ATP hydrolysis, resulting in the stabilization of the ATP-bound form of Hsp90 [12].”
BackgroundA Dynamic View of ATP-coupled Functioning Cycle of Hsp90 N-terminal Domain
Zhang, H., Zhou, C., Chen, W., Xu, Y., Shi, Y., Wen, Y., & Zhang, N. (2015) · Scientific Reports · doi:10.1038/srep09542 · Cited by 43 · see citing works
Blacklock, K. M., & Verkhivker, G. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071936 · Cited by 38 · see citing works
Echeverría, P. C., Figueras, M. J., Vogler, M., Kriehuber, T., de Miguel, N., Deng, B., Dalmasso, M. C., Matthews, D. E., Matrajt, M., Haslbeck, M., et al. (2010) · Molecular and Biochemical Parasitology · doi:10.1016/j.molbiopara.2010.04.004 · Cited by 36 · see citing works
“In higher eukaryotes Hip is a marker of the early Hsp90-heterocomplex, whereas p23 binds to Hsp90 dimmers at a later stage [8,13,14].”
BackgroundDifferences in conformational dynamics within the Hsp90 chaperone family reveal mechanistic insights
Graf, C., Lee, C., Meier-Andrejszki, L. E., Nguyễn, M. T., & Mayer, M. P. (2014) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2014.00004 · Cited by 40 · see citing works
Sun, L., Prince, T. L., Manjarrez, J. R., Scroggins, B. T., & Matts, R. L. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.03.014 · Cited by 37 · see citing works
“However, p23 has been reported to bind at a stoichiometry of one molecule of p23 per Hsp90 dimer [8,42].”
BackgroundHeterozygous Yeast Deletion Collection Screens Reveal Essential Targets of Hsp90
Franzosa, E. A., Albanèse, V., Frydman, J., Xia, Y., & McClellan, A. J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028211 · Cited by 31 · see citing works
Tebbenkamp, A. T. N., & Borchelt, D. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013675 · Cited by 36 · see citing works
“Genes with high levels of variation in expression include Nudc, Ptges3, Ptplad1, and Tomm70a. Ptges3 is also thought to play a major role in protein folding by locking HSPC in an ATP-dependent state which has high affinity for client proteins”
BackgroundEcheverría, P. C., Briand, P.-A., & Picard, D. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.01099-15 · Cited by 39 · see citing works
“60 61 One of the most extensively characterized component of the Hsp90 core machinery 62 is the co-chaperone p23 (18-20), encoded by the gene PTGES3 in mammals.”
BackgroundHsp90 Co-chaperones Form Plastic Genetic Networks Adapted to Client Maturation
Biebl, M. M., Riedl, M., & Büchner, J. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108063 · Cited by 36 · see citing works
Pullen, L., & Bolon, D. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.223131 · Cited by 32 · see citing works
General Structural and Functional Features of Molecular Chaperones.
Edkins, A., & Boshoff, A. (2021) · Advances in Experimental Medicine and Biology · doi:10.1007/978-94-007-7438-4_2 · Cited by 32 · see citing works
Castelli, M., Marchetti, F., Osuna, S., Oliveira, A. S. F., Mulholland, A. J., Serapian, S. A., & Colombo, G. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c11396 · Cited by 38 · see citing works
The Role of p23, Hop, Immunophilins, and Other Co-chaperones in Regulating Hsp90 Function
Cox, M. B., & Johnson, J. L. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-295-3_4 · Cited by 31 · see citing works
Regulatory Mechanisms of Hsp90
Prodromou, C. (2017) · Biochemistry & Molecular Biology Journal · doi:10.21767/2471-8084.100030 · Cited by 31 · see citing works
“In contrast, the ATPase activity of Hsp90 is slowed by the co-chaperone Sba1 [81], although the human orthologue p23 shows a more robust inhibition [82].”
BackgroundAbbasi, M., Sadeghi-aliabadi, H., & Amanlou, M. (2018) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2017.1326319 · Cited by 28
“Finally, ATP is hydrolyzed, the complex is altered and the client protein is folded (McLaughlin et al., 2006).”
BackgroundTherapeutic Strategies for Restoring Tau HomeostasisPreprint
Young, Z. T., Mok, S., & Gestwicki, J. E. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024612 · Cited by 31 · see citing works
“The co-chaperone p23, which binds to the N-terminal ATP-binding domain, also stabilizes the closed state of Hsp90 and traps substrate clients while accelerating ATP hydrolysis (McLaughlin et al. 2006).”
BackgroundAbbasi, M., Sadeghi-aliabadi, H., & Amanlou, M. (2017) · DARU Journal of Pharmaceutical Sciences · doi:10.1186/s40199-017-0182-0 · Cited by 28
Tosylcyclonovobiocic acids promote cleavage of the hsp90-associated cochaperone p23.
Radanyi, C., Bras, G. L., Bouclier, C., Messaoudi, S., Peyrat, J., Brion, J., Alami, M., & Renoir, J. (2009) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2008.12.102 · Cited by 28 · see citing works
The Potential of Hsp90 in Targeting Pathological Pathways in Cardiac Diseases
Roberts, R. J., Hallee, L., & Lam, C. K. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11121373 · Cited by 26 · see citing works
“protein maturation due to its increased client affinity [30,31].”
BackgroundProteomic interrogation of HSP90 and insights for medical research
Weidenauer, L., Wang, T., Joshi, S., Chiosis, G., & Quadroni, M. (2017) · Expert Review of Proteomics · doi:10.1080/14789450.2017.1389649 · Cited by 25 · see citing works
The C-terminal region of the human p23 chaperone modulates its structure and function
Seraphim, T. V., Gava, L. M., Mokry, D. Z., Cagliari, T. C., Barbosa, L. R. S., Ramos, C. H. I., & Borges, J. C. (2015) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2014.10.015 · Cited by 27 · see citing works
The helix 1–3 loop in the glucocorticoid receptor LBD is a regulatory element for FKBP cochaperones
Cluning, C., Ward, B. K., Rea, S. L., Arulpragasam, A., Fuller, P. J., & Ratajczak, T. (2013) · Molecular Endocrinology · doi:10.1210/me.2012-1023 · Cited by 26 · see citing works
- Authors
- McLaughlin, S. H., Sobott, F., Yao, Z.-P., Zhang, W., Nielsen, P. R., Grossmann, J. G., Laue, E. D., Robinson, C. V., & Jackson, S. E.
- Affiliations
- University of Cambridge (GB)
- Daresbury Laboratory (GB)
- Corresponding author
- McLaughlin, Stephen H.
- Jackson, Sophie E.
- ORCID
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 356
- Issue
- 3
- Pages
- 746-758
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W2070981149
- Cited by
- 196
- References
- 57
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 2 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 7 · 2019: 3 · 2018: 10 · 2017: 14 · 2016: 11 · 2015: 9 · 2014: 14 · 2013: 14 · 2012: 15
- FWCI
- 3.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Leverhulme Trust
- 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, p23, co-chaperones, ATPase activity, HSP90β, AMP-PNP, mixed-type inhibition, protein-protein interaction, ATP binding, chaperone mechanism
- MeSH terms
- Adenosine Triphosphatases, Adenylyl Imidodiphosphate, Calorimetry, Chromatography, Gel, DNA-Binding Proteins, Humans, Kinetics, Protein Binding, Protein Conformation, Thermodynamics, Molecular Chaperones, HSP90 Heat-Shock Proteins, Dimerization, Protein Subunits
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