Hsp90 Quaternary Structures and the Chaperone Cycle: Highly Flexible Dimeric and Oligomeric Structures and Their Regulation by Co-Chaperones

Author(s): Eléonore Lepvrier, Daniel Thomas, Cyrille Garnier*.

Journal Name: Current Proteomics

Volume 16 , Issue 1 , 2019

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Abstract:

Proposed models of the function of Hsp90 are characterised by high flexibility of the dimeric state and conformational changes regulated by both nucleotide binding and hydrolysis, and by co-chaperone interactions. In addition to its dimeric state, Hsp90 self-associates upon particular stimuli. The Hsp90 dimer is the building block up to the hexamer that we named “cosy nest”, and the dodecamer results from the association of two hexamers. Oligomers exhibit chaperone activity, but their exact mechanism of action has not yet been determined. One of the best ways to elucidate how oligomers might operate is to study their interactions with co-chaperone proteins known to regulate the Hsp90 chaperone cycle, such as p23 and Aha1. In this review, we summarise recent results and conclude that Hsp90 oligomers are key players in the chaperone cycle. Crucible-shaped quaternary structures likely provide an ideal environment for client protein accommodation and folding, as is the case for other Hsp families. Confirmation of the involvement of Hsp90 oligomers in the chaperone cycle and a better understanding of their functionality will allow us to address some of the more enigmatic aspects of Hsp90 activity. Utilising this knowledge, future work will highlight how Hsp90 oligomers and co-chaperones cooperate to build the structures required to fold or refold numerous different client proteins.

Keywords: Hsp90, chaperone cycle, oligomers, co-chaperone regulation, self-association, protein flexibility.

[1]
Pearl, L.H.; Prodromou, C. Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu. Rev. Biochem., 2006, 75, 271-294.
[2]
Nollen, E.A.; Morimoto, R.I. Chaperoning signaling pathways: Molecular chaperones as stress-sensing ‘heat shock’ proteins. J. Cell Sci., 2002, 115(Pt 14), 2809-2816.
[3]
Lai, B.T.; Chin, N.W.; Stanek, A.E.; Keh, W.; Lanks, K.W. Quantitation and intracellular localization of the 85K heat shock protein by using monoclonal and polyclonal antibodies. Mol. Cell. Biol., 1984, 4(12), 2802-2810.
[4]
Hickey, E.; Brandon, S.E.; Sadis, S.; Smale, G.; Weber, L.A. Molecular cloning of sequences encoding the human heat-shock proteins and their expression during hyperthermia. Gene, 1986, 43(1-2), 147-154.
[5]
Radanyi, C.; Renoir, J.M.; Sabbah, M.; Baulieu, E.E. Chick heat-shock protein of Mr = 90,000, free or released from progesterone receptor, is in a dimeric form. J. Biol. Chem., 1989, 264(5), 2568-2573.
[6]
Garnier, C.; Lafitte, D.; Jorgensen, T.J.; Jensen, O.N.; Briand, C.; Peyrot, V. Phosphorylation and oligomerization states of native pig brain HSP90 studied by mass spectrometry. Eur. J. Biochem., 2001, 268(8), 2402-2407.
[7]
Prodromou, C.; Roe, S.M.; O’Brien, R.; Ladbury, J.E.; Piper, P.W.; Pearl, L.H. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell, 1997, 90(1), 65-75.
[8]
Prodromou, C.; Roe, S.M.; Piper, P.W.; Pearl, L.H. A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone. Nat. Struct. Biol., 1997, 4(6), 477-482.
[9]
Silva, K.P.; Seraphim, T.V.; Borges, J.C. Structural and functional studies of Leishmania braziliensis Hsp90. Biochim. Biophys. Acta, 2013, 1834(1), 351-361.
[10]
Prodromou, C.; Panaretou, B.; Chohan, S.; Siligardi, G.; O’Brien, R.; Ladbury, J.E.; Roe, S.M.; Piper, P.W.; Pearl, L.H. The ATPase cycle of Hsp90 drives a molecular ‘clamp’ via transient dimerization of the N-terminal domains. EMBO J., 2000, 19(16), 4383-4392.
[11]
Ratzke, C.; Mickler, M.; Hellenkamp, B.; Buchner, J.; Hugel, T. Dynamics of heat shock protein 90 C-terminal dimerization is an important part of its conformational cycle. Proc. Natl. Acad. Sci. USA, 2010, 107(37), 16101-16106.
[12]
Meyer, P.; Prodromou, C.; Hu, B.; Vaughan, C.; Roe, S.M.; Panaretou, B.; Piper, P.W.; Pearl, L.H. Structural and functional analysis of the middle segment of hsp90: Implications for ATP hydrolysis and client protein and cochaperone interactions. Mol. Cell, 2003, 11(3), 647-658.
[13]
Minami, Y.; Kimura, Y.; Kawasaki, H.; Suzuki, K.; Yahara, I. The carboxy-terminal region of mammalian HSP90 is required for its dimerization and function in vivo. Mol. Cell. Biol., 1994, 14(2), 1459-1464.
[14]
Marcu, M.G.; Chadli, A.; Bouhouche, I.; Catelli, M.; Neckers, L.M. The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone. J. Biol. Chem., 2000, 275(47), 37181-37186.
[15]
Garnier, C.; Lafitte, D.; Tsvetkov, P.O.; Barbier, P.; Leclerc-Devin, J.; Millot, J.M.; Briand, C.; Makarov, A.A.; Catelli, M.G.; Peyrot, V. Binding of ATP to heat shock protein 90: Evidence for an ATP-binding site in the C-terminal domain. J. Biol. Chem., 2002, 277(14), 12208-12214.
[16]
Bron, P.; Giudice, E.; Rolland, J.P.; Buey, R.M.; Barbier, P.; Diaz, J.F.; Peyrot, V.; Thomas, D.; Garnier, C. Apo-Hsp90 coexists in two open conformational states in solution. Biol. Cell, 2008, 100(7), 413-425.
[17]
Seraphim, T.V.; Silva, K.P.; Dores-Silva, P.R.; Barbosa, L.R.; Borges, J.C. Insights on the structural dynamics of Leishmania braziliensis Hsp90 molecular chaperone by small angle X-ray scattering. Int. J. Biol. Macromol., 2017, 97, 503-512.
[18]
Ali, M.M.; Roe, S.M.; Vaughan, C.K.; Meyer, P.; Panaretou, B.; Piper, P.W.; Prodromou, C.; Pearl, L.H. Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature, 2006, 440(7087), 1013-1017.
[19]
Shiau, A.K.; Harris, S.F.; Southworth, D.R.; Agard, D.A. Structural analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements. Cell, 2006, 127(2), 329-340.
[20]
Richter, K.; Buchner, J. Hsp90: Twist and fold. Cell, 2006, 127(2), 251-253.
[21]
Li, J.; Buchner, J. Structure, function and regulation of the hsp90 machinery. Biomed. J., 2013, 36(3), 106-117.
[22]
Rohl, A.; Rohrberg, J.; Buchner, J. The chaperone Hsp90: Changing partners for demanding clients. Trends Biochem. Sci., 2013, 38(5), 253-262.
[23]
Li, J.; Richter, K.; Reinstein, J.; Buchner, J. Integration of the accelerator Aha1 in the Hsp90 co-chaperone cycle. Nat. Struct. Mol. Biol., 2013, 20(3), 326-331.
[24]
Mayer, M.P.; Le Breton, L. Hsp90: Breaking the symmetry. Mol. Cell, 2015, 58(1), 8-20.
[25]
Roe, S.M.; Ali, M.M.; Meyer, P.; Vaughan, C.K.; Panaretou, B.; Piper, P.W.; Prodromou, C.; Pearl, L.H. The mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37). Cell, 2004, 116(1), 87-98.
[26]
Prodromou, C.; Siligardi, G.; O’Brien, R.; Woolfson, D.N.; Regan, L.; Panaretou, B.; Ladbury, J.E.; Piper, P.W.; Pearl, L.H. Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones. EMBO J., 1999, 18(3), 754-762.
[27]
Panaretou, B.; Siligardi, G.; Meyer, P.; Maloney, A.; Sullivan, J.K.; Singh, S.; Millson, S.H.; Clarke, P.A.; Naaby-Hansen, S.; Stein, R.; Cramer, R.; Mollapour, M.; Workman, P.; Piper, P.W.; Pearl, L.H.; Prodromou, C. Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1. Mol. Cell, 2002, 10(6), 1307-1318.
[28]
Chen, S.; Smith, D.F. Hop as an adaptor in the heat shock protein 70 (Hsp70) and hsp90 chaperone machinery. J. Biol. Chem., 1998, 273(52), 35194-35200.
[29]
Nemoto, T.; Sato, N. Oligomeric forms of the 90-kDa heat shock protein. Biochem. J., 1998, 330(Pt 2), 989-995.
[30]
Soti, C.; Radics, L.; Yahara, I.; Csermely, P. Interaction of vanadate oligomers and permolybdate with the 90-kDa heat-shock protein, Hsp90. Eur. J. Biochem., 1998, 255(3), 611-617.
[31]
Garnier, C.; Barbier, P.; Devred, F.; Rivas, G.; Peyrot, V. Hydrodynamic properties and quaternary structure of the 90 kDa heat-shock protein: Effects of divalent cations. Biochemistry, 2002, 41(39), 11770-11778.
[32]
Jakob, U.; Meyer, I.; Bugl, H.; Andre, S.; Bardwell, J.C.; Buchner, J. Structural organization of procaryotic and eucaryotic Hsp90. Influence of divalent cations on structure and function. J. Biol. Chem., 1995, 270(24), 14412-14419.
[33]
Garnier, C.; Barbier, P.; Gilli, R.; Lopez, C.; Peyrot, V.; Briand, C. Heat-shock protein 90 (hsp90) binds in vitro to tubulin dimer and inhibits microtubule formation. Biochem. Biophys. Res. Commun., 1998, 250(2), 414-419.
[34]
Chadli, A.; Ladjimi, M.M.; Baulieu, E.E.; Catelli, M.G. Heat-induced oligomerization of the molecular chaperone Hsp90. Inhibition by ATP and geldanamycin and activation by transition metal oxyanions. J. Biol. Chem., 1999, 274(7), 4133-4139.
[35]
Moullintraffort, L.; Bruneaux, M.; Nazabal, A.; Allegro, D.; Giudice, E.; Zal, F.; Peyrot, V.; Barbier, P.; Thomas, D.; Garnier, C. Biochemical and biophysical characterization of the Mg2+-induced 90-kDa heat shock protein oligomers. J. Biol. Chem., 2010, 285(20), 15100-15110.
[36]
Lee, C.C.; Lin, T.W.; Ko, T.P.; Wang, A.H. The hexameric structures of human heat shock protein 90. PLoS One, 2011, 6(5), e19961.
[37]
Richter, K.; Soroka, J.; Skalniak, L.; Leskovar, A.; Hessling, M.; Reinstein, J.; Buchner, J. Conserved conformational changes in the ATPase cycle of human Hsp90. J. Biol. Chem., 2008, 283(26), 17757-17765.
[38]
Pullen, L.; Bolon, D.N. Enforced N-domain proximity stimulates Hsp90 ATPase activity and is compatible with function in vivo. J. Biol. Chem., 2011, 286(13), 11091-11098.
[39]
Yonehara, M.; Minami, Y.; Kawata, Y.; Nagai, J.; Yahara, I. Heat-induced chaperone activity of HSP90. J. Biol. Chem., 1996, 271(5), 2641-2645.
[40]
Cha, J.Y.; Ahn, G.; Kim, J.Y.; Kang, S.B.; Kim, M.R.; Su’udi, M.; Kim, W.Y.; Son, D. Structural and functional differences of cytosolic 90-kDa heat-shock proteins (Hsp90s) in Arabidopsis thaliana. Plant Physiol. Biochem., 2013, 70, 368-373.
[41]
Schirmer, C.; Lepvrier, E.; Duchesne, L.; Decaux, O.; Thomas, D.; Delamarche, C.; Garnier, C. Hsp90 directly interacts, in vitro, with amyloid structures and modulates their assembly and disassembly. Biochim. Biophys. Acta, 2016, 1860(11 Pt A), 2598-2609.
[42]
Lepvrier, E.; Moullintraffort, L.; Nigen, M.; Goude, R.; Allegro, D.; Barbier, P.; Peyrot, V.; Thomas, D.; Nazabal, A.; and Garnier, C. Hsp90 oligomers interacting with the aha1 cochaperone: An outlook for the Hsp90 chaperone machineries. Anal. Chem., 2015, 87(14), 7043-7051.
[43]
Lepvrier, E.; Nigen, M.; Moullintraffort, L.; Chat, S.; Allegro, D.; Barbier, P.; Thomas, D.; Nazabal, A.; Garnier, C. Hsp90 oligomerization process: How can p23 drive the chaperone machineries? Biochim. Biophys. Acta, 2015, 1854(10 Pt A), 1412-1424.
[44]
Mayer, M.P.; Nikolay, R.; Bukau, B. Aha, another regulator for hsp90 chaperones. Mol. Cell, 2002, 10(6), 1255-1256.
[45]
Lotz, G.P.; Lin, H.; Harst, A.; Obermann, W.M. Aha1 binds to the middle domain of Hsp90, contributes to client protein activation, and stimulates the ATPase activity of the molecular chaperone. J. Biol. Chem., 2003, 278(19), 17228-17235.
[46]
Seraphim, T.V.; Alves, M.M.; Silva, I.M.; Gomes, F.E.; Silva, K.P.; Murta, S.M.; Barbosa, L.R.; Borges, J.C. Low resolution structural studies indicate that the activator of Hsp90 ATPase 1 (Aha1) of Leishmania braziliensis has an elongated shape which allows its interaction with both N- and M-domains of Hsp90. PLoS One, 2013, 8(6), e66822.
[47]
Koulov, A.V.; LaPointe, P.; Lu, B.; Razvi, A.; Coppinger, J.; Dong, M.Q.; Matteson, J.; Laister, R.; Arrowsmith, C.; Yates, J.R.; Balch, W.E. Biological and structural basis for Aha1 regulation of Hsp90 ATPase activity in maintaining proteostasis in the human disease cystic fibrosis. Mol. Biol. Cell, 2010, 21(6), 871-884.
[48]
Blacklock, K.; Verkhivker, G.M. Differential modulation of functional dynamics and allosteric interactions in the Hsp90-cochaperone complexes with p23 and Aha1: A computational study. PLoS One, 2013, 8(8), e71936.
[49]
Retzlaff, M.; Hagn, F.; Mitschke, L.; Hessling, M.; Gugel, F.; Kessler, H.; Richter, K.; Buchner, J. Asymmetric activation of the hsp90 dimer by its cochaperone aha1. Mol. Cell, 2010, 37(3), 344-354.
[50]
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. The co-chaperone p23 arrests the Hsp90 ATPase cycle to trap client proteins. J. Mol. Biol., 2006, 356(3), 746-758.
[51]
Karagoz, G.E.; Duarte, A.M.; Ippel, H.; Uetrecht, C.; Sinnige, T.; van Rosmalen, M.; Hausmann, J.; Heck, A.J.; Boelens, R.; Rudiger, S.G. N-terminal domain of human Hsp90 triggers binding to the cochaperone p23. Proc. Natl. Acad. Sci. USA, 2011, 108(2), 580-585.
[52]
Harst, A.; Lin, H.; Obermann, W.M. Aha1 competes with Hop, p50 and p23 for binding to the molecular chaperone Hsp90 and contributes to kinase and hormone receptor activation. Biochem. J., 2005, 387(Pt 3), 789-796.
[53]
Alvira, S.; Cuellar, J.; Rohl, A.; Yamamoto, S.; Itoh, H.; Alfonso, C.; Rivas, G.; Buchner, J.; Valpuesta, J.M. Structural characterization of the substrate transfer mechanism in Hsp70/ Hsp90 folding machinery mediated by Hop. Nat. Commun., 2014, 5, 5484.


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VOLUME: 16
ISSUE: 1
Year: 2019
Page: [5 - 11]
Pages: 7
DOI: 10.2174/1570164615666180522095147
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