Hsp90

Hsp90

Pfam_box
Symbol = Hsp90 NTD
Name = Hsp90, N-terminal domain


width = 270px
caption = Solid ribbon model of the yeast Hsp90-dimer (α-helices = red, β-sheets = cyan, loops = grey) in complex with ATP (red stick diagram) based on PDB|2CG9.
Pfam= PF02518
InterPro= IPR003594
SMART=
PROSITE = PDOC00270
SCOP = d.122.1.1
SCOP = 1AH6
TCDB =
PDB = PDB2|1A4H, PDB2|1AH6, PDB2|1AH8, PDB2|1AM1, PDB2|1AMW, PDB2|1BGQ, PDB2|1BYQ, PDB2|1OSF, PDB2|1QY5, PDB2|1QY8, PDB2|1QYE, PDB2|1TBW, PDB2|1TC0, PDB2|1U0Y, PDB2|1U2O, PDB2|1US7, PDB2|1UY6, PDB2|1UY7, PDB2|1UY8, PDB2|1UY9, PDB2|1UYC, PDB2|1UYD, PDB2|1UYE, PDB2|1UYF, PDB2|1UYG, PDB2|1UYH, PDB2|1UYI, PDB2|1UYK, PDB2|1UYL, PDB2|1UYM, PDB2|1Y4S, PDB2|1Y4U, PDB2|1YC3, PDB2|1YER, PDB2|1YES, PDB2|1YET, PDB2|1YSZ, PDB2|1YT0, PDB2|1YT1, PDB2|1YT1, PDB2|1YT2, PDB2|1ZW9, PDB2|1ZWH, PDB2|2AKP, PDB2|2BRC, PDB2|2BRE, PDB2|2BSM, PDB2|2BT0, PDB2|2BYH, PDB2|2BYI, PDB2|2BZ5, PDB2|2CCS, PDB2|2CCT, PDB2|2CCU, PDB2|2CDD, PDB2|2CG9, PDB2|2CGF, PDB2|2ESA, PDB2|2EXL, PDB2|2FWY, PDB2|2FWZ, PDB2|2FXS, PDB2|2FYP, PDB2|2GFD, PDB2|2GQP, PDB2|2H55, PDB2|2H8M, PDB2|2HCH, PDB2|2HG1, PDB2|2IOP, PDB2|2IOQ, PDB2|2IOR, PDB2|2IWS, PDB2|2IWU, PDB2|2IWX, PDB2|2O1U, PDB2|2O1V, PDB2|2O1W, PDB2|2QF6, PDB2|2QFO, PDB2|2QG0, PDB2|2QG2, PDB2|2UWD, PDB2|2VCI, PDB2|2VCJ, PDB2|2VWC, PDB2|3D0B

Pfam_box
Symbol = Hsp90 MD
Name = Hsp90 middle domain
Pfam= PF00183
InterPro= IPR001404
SMART=
PROSITE = PDOC00270
SCOP = d.14.1.8
SCOP = 1hk7
TCDB =
PDB = PDB2|1HK7, PDB2|1USU, PDB2|1USV, PDB2|1Y4S, PDB2|1Y4U, PDB2|2CG9, PDB2|2CGE, PDB2|2GQ0, PDB2|2IOP, PDB2|2IOQ, PDB2|2O1T, PDB2|2O1U, PDB2|2O1V, PDB2|2O1W

Pfam_box
Symbol = Hsp90 CTD
Name = Hsp90 C-terminal domain
Pfam= PF00183
InterPro= IPR001404
SMART=
PROSITE = PDOC00270
SCOP = d.271.1.1
SCOP = 1sf8
TCDB =
PDB = PDB2|1SF8, PDB2|2CG9, PDB2|2CGE, PDB2|2IOP, PDB2|2IOQ, PDB2|2O1T, PDB2|2O1U, PDB2|2O1V, PDB2|2O1W

Hsp90 (heat shock protein 90) is a molecular chaperone and is one of the most abundant proteins expressed in cells.cite journal | author = Csermely P, Schnaider T, Soti C, Prohászka Z, Nardai G | title = The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review | journal = Pharmacol. Ther. | volume = 79 | issue = 2 | pages = 129–68 | year = 1998 | month = August | pmid = 9749880 | doi = 10.1016/S0163-7258(98)00013-8 | url = | issn = ] It is a member of the heat shock protein family which is upregulated in response to stress. Hsp90 is found in bacteria and all branches of eukarya, but it is apparently absent in archaea.cite journal | author = Chen B, Zhong D, Monteiro A | title = Comparative genomics and evolution of the Hsp90 family of genes across all kingdoms of organisms | journal = BMC Genomics | volume = 7 | issue = | pages = 156 | year = 2006 | pmid = 16780600 | pmc = 1525184 | doi = 10.1186/1471-2164-7-156 | url = ] Whereas cytoplasmic Hsp90 is essential for viability under all conditions in eukaryotes, the bacterial homologue HtpG is dispensable under non-heat stress conditions.cite journal | author = Thomas JG, Baneyx F | title = Roles of the Escherichia coli small heat shock proteins IbpA and IbpB in thermal stress management: comparison with ClpA, ClpB, and HtpG In vivo | journal = J. Bacteriol. | volume = 180 | issue = 19 | pages = 5165–72 | year = 1998 | month = October | pmid = 9748451 | pmc = 107554 | url = | issn = ]

Introduction

Heat shock proteins, as a class, are among the most highly expressed cellular proteins across all species. As their name implies, heat shock proteins protect cells when stressed by elevated temperatures. They account for 1–2% of total protein in unstressed cells. However when cells are heated, the fraction of heat shock proteins increases to 4–6% of cellular proteins.cite journal | author = Crevel G, Bates H, Huikeshoven H, Cotterill S | title = The Drosophila Dpit47 protein is a nuclear Hsp90 co-chaperone that interacts with DNA polymerase alpha | journal = J. Cell. Sci. | volume = 114 | issue = Pt 11 | pages = 2015–25 | year = 2001 | month = June | pmid = 11493638 | url = http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=11493638 | issn = ]

Heat shock protein 90 (Hsp90) is one of the most common of the heat related proteins. The protein is named "HSP" for obvious reasons whereas the "90" comes from the fact that it weighs roughly 90 kiloDaltons. A 90 kDa size protein is considered a fairly large for a non-fibrous protein.

The function of Hsp90 includes assisting in protein folding, cell signaling, and tumor repression. This protein was first isolated by extracting proteins from stressed cells. These cells were stressed by heating, dehydrating or by other means, all of which caused the cell’s proteins to begin to denature.cite journal | author = Prodromou C, Panaretou B, Chohan S, Siligardi G, O'Brien R, Ladbury JE, Roe SM, Piper PW, Pearl LH | title = The ATPase cycle of Hsp90 drives a molecular 'clamp' via transient dimerization of the N-terminal domains | journal = EMBO J. | volume = 19 | issue = 16 | pages = 4383–92 | year = 2000 | month = August | pmid = 10944121 | pmc = 302038 | doi = 10.1093/emboj/19.16.4383 | url = ] As discussed in more detail below, researchers later realized that Hsp90 has other essential functions in unstressed cells.

Isoforms

Hsp90 is highly conserved and expressed in a variety of different organisms from bacteria to mammals – including the prokaryotic analogue htpG (high temperature protein G) with 40% sequence identity and 55% similarity to the human protein. Yeast Hsp90 is 60% identical to human Hsp90α.

In mammalian cells, there are two or more genes encoding cytosolic Hsp90 homologues, with the human Hsp90α showing 85% sequence identity to Hsp90β.cite journal | author = Chen B, Piel WH, Gui L, Bruford E, Monteiro A | title = The Hsp90 family of genes in the human genome: insights into their divergence and evolution | journal = Genomics | volume = 86 | issue = 6 | pages = 627–37 | year = 2005 | month = December | pmid = 16269234 | doi = 10.1016/j.ygeno.2005.08.012 | url = | issn = ] The α- and the β-forms are thought to be the result of a gene duplication event that occurred millions of years ago.

The five functional human genes encoding Hsp90 protein isoforms are listed below:

There are 12 human pseudogenes (non-functional genes) that encode additional Hsp90 isoforms which are not expressed as proteins.

Recently, a membrane associated variant of cytosolic Hsp90, lacking an ATP-binding site, has been identified and was named Hsp90N.cite journal | author = Grammatikakis N, Vultur A, Ramana CV, Siganou A, Schweinfest CW, Watson DK, Raptis L | title = The role of Hsp90N, a new member of the Hsp90 family, in signal transduction and neoplastic transformation | journal = J. Biol. Chem. | volume = 277 | issue = 10 | pages = 8312–20 | year = 2002 | month = March | pmid = 11751906 | doi = 10.1074/jbc.M109200200 | url = ] Hsp90N is a splice variant of HSP90AA1.

tructure

Common features

The overall structure of Hsp90 is similar to other proteins in that it contains all of the common secondary structural elements (i.e., alpha helixes, beta pleated sheets and random coils). Being a cytoplasmic protein requires that the protein be globular in structure, that is largely non-polar on the inside and polar on the outside, so as to be dissolved by water. Hsp90 contains nine helices and eight anti-parallel beta pleated sheets, which combine to form several alpha/beta sandwiches. The 310 helices make up approximately 11% of the protein's amino acid residues, which is much higher than the average 4% in other proteins.cite journal | author = Goetz MP, Toft DO, Ames MM, Erlichman C | title = The Hsp90 chaperone complex as a novel target for cancer therapy | journal = Ann. Oncol. | volume = 14 | issue = 8 | pages = 1169–76 | year = 2003 | month = August | pmid = 12881371 | url = | doi = 10.1093/annonc/mdg316 ]

Domain structure

Hsp90 consists of four structural domains:cite journal | author = Pearl LH, Prodromou C | title = Structure and in vivo function of Hsp90 | journal = Curr. Opin. Struct. Biol. | volume = 10 | issue = 1 | pages = 46–51 | year = 2000 | month = February | pmid = 10679459 | url = | doi = 10.1016/S0959-440X(99)00047-0 ] cite journal | author = Prodromou C, Pearl LH | title = Structure and functional relationships of Hsp90 | journal = Curr Cancer Drug Targets | volume = 3 | issue = 5 | pages = 301–23 | year = 2003 | month = October | pmid = 14529383 | url = | doi = 10.2174/1568009033481877 ] cite journal | author = Pearl LH, Prodromou C | title = Structure, function, and mechanism of the Hsp90 molecular chaperone | journal = Adv. Protein Chem. | volume = 59 | issue = | pages = 157–86 | year = 2001 | pmid = 11868271 | url = | doi = 10.1016/S0065-3233(01)59005-1 ]
* a highly conserved N-terminal (NTD) domain of ~25 kDa,
* a "charged linker" region, that connects the N-terminus with the middle domain.
* a middle domain (MD) of ~40 kDa,
* a C-terminal domain (CTD) of ~12 kDa and

Crystal structures are available for the N-terminal domain of yeast and human Hsp90,cite journal | author = Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP | title = Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent | journal = Cell | volume = 89 | issue = 2 | pages = 239–50 | year = 1997 | month = April | pmid = 9108479 | url = | doi = 10.1016/S0092-8674(00)80203-2 ] cite journal | author = Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH | title = Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone | journal = Cell | volume = 90 | issue = 1 | pages = 65–75 | year = 1997 | month = July | pmid = 9230303 | url = | doi = 10.1016/S0092-8674(00)80314-1 ] cite journal | author = Prodromou C, Roe SM, Piper PW, Pearl LH | title = A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone | journal = Nat. Struct. Biol. | volume = 4 | issue = 6 | pages = 477–82 | year = 1997 | month = June | pmid = 9187656 | url = | doi = 10.1038/nsb0697-477 ] for complexes of the N-terminus with inhibitors and nucleotides, and for the middle domain of yeast Hsp90.cite journal | author = Meyer P, Prodromou C, Hu B, Vaughan C, Roe SM, Panaretou B, Piper PW, Pearl LH | title = Structural and functional analysis of the middle segment of hsp90: implications for ATP hydrolysis and client protein and cochaperone interactions | journal = Mol. Cell | volume = 11 | issue = 3 | pages = 647–58 | year = 2003 | month = March | pmid = 12667448 | url = | doi = 10.1016/S1097-2765(03)00065-0 ] Recently structures for full length Hsp90 from "E. coli" (PDB2|2IOP, PDB2|2IOQ),cite journal | author = Shiau AK, Harris SF, Southworth DR, Agard DA | title = Structural Analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements | journal = Cell | volume = 127 | issue = 2 | pages = 329–40 | year = 2006 | month = October | pmid = 17055434 | doi = 10.1016/j.cell.2006.09.027 | url = | issn = ] yeast (PDB2|2CG9, PDB2|2CGE),cite journal | author = Ali MM, Roe SM, Vaughan CK, Meyer P, Panaretou B, Piper PW, Prodromou C, Pearl LH' | title = Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex | journal = Nature | volume = 440 | issue = 7087 | pages = 1013–7 | year = 2006 | month = April | pmid = 16625188 | doi = 10.1038/nature04716 | url = ] and the dog endoplasmic reticulum (PDB2|2O1U, PDB2|2O1V)cite journal | author = Dollins DE, Warren JJ, Immormino RM, Gewirth DT | title = Structures of GRP94-nucleotide complexes reveal mechanistic differences between the hsp90 chaperones | journal = Mol. Cell | volume = 28 | issue = 1 | pages = 41–56 | year = 2007 | month = October | pmid = 17936703 | doi = 10.1016/j.molcel.2007.08.024 | url = | issn = ] were elucidated.cite journal | author = Wandinger SK, Richter K, Buchner J | title = The hsp90 chaperone machinery | journal = J. Biol. Chem. | volume = 283 | issue = 27 | pages = 18473–7 | year = 2008 | month = July | pmid = 18442971 | doi = 10.1074/jbc.R800007200 | url = | issn = ]

Hsp90 forms homodimers where the contact sites are localized within the C-terminus in the open conformation of the dimer. The N-termini also come in contact in the closed conformation of the dimer.cite journal | author = Meyer P, Prodromou C, Hu B, Vaughan C, Roe SM, Panaretou B, Piper PW, Pearl LH. | title = Structural and functional analysis of the middle segment of hsp90: implications for ATP hydrolysis and client protein and cochaperone interactions | journal = Mol. Cell | volume = 11 | issue = 3 | pages = 647–58 | year = 2003 | month = March | pmid = 12667448 | url = | doi = 10.1016/S1097-2765(03)00065-0 ]

N-terminal domain

The N-terminal domain shows high homology not only amongst members of the Hsp90 chaperone family, but also to members of the ATPase/kinase GHKL (Gyrase, Hsp90, Histidine Kinase, MutL) superfamily.

A common binding pocket for ATP and the inhibitor geldanamycin is situated in the N-terminal domain. Amino acids that are directly involved in the interaction with ATP are Leu34, Asn37, Asp79, Asn92, Lys98, Gly121, and Phe124. In addition, Mg2+ and a several water molecules form bridging electrostatic and hydrogen bonding interactions respectively between Hsp90 and ATP. In addition, Glu33 is required for ATP hydrolysis.

Middle domain

The middle domain is divided into three regions:
*a 3-layer α-β-α sandwich,
*a 3-turn α-helix and irregular loops, and
*a 6-turn α-helix. The MD is also involved in client protein binding. For example proteins known to interact this the Hsp90 MD include PKB/Akt1, eNOS,cite journal | author = Fontana J, Fulton D, Chen Y, Fairchild TA, McCabe TJ, Fujita N, Tsuruo T, Sessa WC | title = Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release | journal = Circ. Res. | volume = 90 | issue = 8 | pages = 866–73 | year = 2002 | month = May | pmid = 11988487 | url = | doi = 10.1161/01.RES.0000016837.26733.BE ] Aha1, Hch1. Furthermore substrate binding (e.g., by Aha1 and Hch1) to the MD is also known to increase the ATPase activity of Hsp90.cite journal | author = Panaretou B, Siligardi G, Meyer P, Maloney A, Sullivan JK, Singh S, Millson SH, Clarke PA, Naaby-Hansen S, Stein R, Cramer R, Mollapour M, Workman P, Piper PW, Pearl LH, Prodromou C | title = Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1 | journal = Mol. Cell | volume = 10 | issue = 6 | pages = 1307–18 | year = 2002 | month = December | pmid = 12504007 | url = | doi = 10.1016/S1097-2765(02)00785-2 ]

C-terminal domain

The C-terminal domain possesses an alternative ATP-binding site, which becomes accessible when the N-terminal Bergerat pocket is occupied.cite journal | author = Marcu MG, Chadli A, Bouhouche I, Catelli M, Neckers LM | title = The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone | journal = J. Biol. Chem. | volume = 275 | issue = 47 | pages = 37181–6 | year = 2000 | month = November | pmid = 10945979 | doi = 10.1074/jbc.M003701200 | url = ] cite journal | author = Söti C, Rácz A, Csermely P | title = A Nucleotide-dependent molecular switch controls ATP binding at the C-terminal domain of Hsp90. N-terminal nucleotide binding unmasks a C-terminal binding pocket | journal = J. Biol. Chem. | volume = 277 | issue = 9 | pages = 7066–75 | year = 2002 | month = March | pmid = 11751878 | doi = 10.1074/jbc.M105568200 | url = ]

At the very C-terminal end of the protein is the tetratricopeptide repeat (TPR) motif recognition site, the conserved MEEVD pentapeptide, that is responsible for the interaction with co-factors such as the immunophilins FKBP51 and FKBP52, the stress induced phosphoprotein 1 (Sti1/Hop), cyclophilin-40, PP5, Tom70, and many more.cite journal | author = Young JC, Obermann WM, Hartl FU | title = Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of hsp90 | journal = J. Biol. Chem. | volume = 273 | issue = 29 | pages = 18007–10 | year = 1998 | month = July | pmid = 9660753 | url = | doi = 10.1074/jbc.273.29.18007 ]

Mechanism

The Hsp90 protein contains three functional domains, the ATP binding, protein binding and dimerizing domain, each of which play a crucial role in the function of the protein.

ATP binding

The region of the protein near the N-terminus has a high affinity ATP binding site. The ATP binds to a sizable cleft in the side of protein, which is 15 Å (1.5 nanometres) deep. This cleft has a high affinity for ATP, and when given a suitable protein substrate, Hsp90 cleaves the ATP into ADP and Pi. Direct inhibitors of ATP binding or allosteric inhibitors of either ATP binding or ATPase activity can block Hsp90 function. ] Another interesting feature of the ATP-binding region of Hsp90 is that it has a “lid” that is open during the ADP-bound state and closed in the ATP-bound state, in the open conformation, the lid has no intraprotein interaction, and when closed comes into contact with several residues.cite journal | author = Wegele H, Müller L, Buchner J | title = Hsp70 and Hsp90--a relay team for protein folding | journal = Rev. Physiol. Biochem. Pharmacol. | volume = 151 | issue = | pages = 1–44 | year = 2004 | pmid = 14740253 | doi = 10.1007/s10254-003-0021-1 | url = ] The contribution of this lid to the activity of Hsp90 has been probed with site-directed mutagenesis. The Ala107Asp mutant stabilizing the closed conformation of the protein through the formation of additional hydrogen bonds substantially increases ATPase activity while leaving the AMP+PnP conformation unchanged.

The ATPase binding region of Hsp90 is currently under intense study, because it is the principal binding site of drugs targeting this protein.cite journal | author = Chiosis G, Caldas Lopes E, Solit D | title = Heat shock protein-90 inhibitors: a chronicle from geldanamycin to today's agents | journal = Curr Opin Investig Drugs | volume = 7 | issue = 6 | pages = 534–41 | year = 2006 | month = June | pmid = 16784024 | doi = | url = | issn = ] Antitumor drugs targeting this section of Hsp90 include the antibiotics geldanamycin,cite journal | author = Pratt WB, Toft DO | title = Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery | journal = Exp. Biol. Med. (Maywood) | volume = 228 | issue = 2 | pages = 111–33 | year = 2003 | month = February | pmid = 12563018 | url = http://www.ebmonline.org/cgi/pmidlookup?view=long&pmid=12563018 | issn = ] herbimycin, radicicol, deguelin,cite journal | author =Oh SH, Woo JK, Yazici YD, Myers JN, Kim WY, Jin Q, Hong SS, Park HJ, Suh YG, Kim KW, Hong WK, Lee HY | title = Structural basis for depletion of heat shock protein 90 client proteins by deguelin | journal = J. Natl. Cancer Inst. | volume = 99 | issue = 12 | pages = 949–61 | year = 2007 | month = June | pmid = 17565155 | doi = 10.1093/jnci/djm007 | url = ] , derrubone,cite journal | author = Hadden MK, Galam L, Gestwicki JE, Matts RL, Blagg BS | title = Derrubone, an inhibitor of the Hsp90 protein folding machinery | journal = J. Nat. Prod. | volume = 70 | issue = 12 | pages = 2014–8 | year = 2007 | month = December | pmid = 18020309 | doi = 10.1021/np070190s | url = ] and macbecin.cite journal | author = Martin CJ, Gaisser S, Challis IR, Carletti I, Wilkinson B, Gregory M, Prodromou C, Roe SM, Pearl LH, Boyd SM, Zhang MQ | title = Molecular characterization of macbecin as an Hsp90 inhibitor | journal = J. Med. Chem. | volume = 51 | issue = 9 | pages = 2853–7 | year = 2008 | month = May | pmid = 18357975 | doi = 10.1021/jm701558c | url = ]

Protein binding

The protein binding region of Hsp90 is located towards the C-terminus of the amino sequence. The Hsp90 protein can adopt two major conformational states. The first is an open ATP-bound state and the second is a closed ADP-bound state. Thus ATP hydrolysis drives what is commonly referred to as a “pincer type” conformational change in the protein binding site.cite journal | author = Grenert JP, Sullivan WP, Fadden P, Haystead TA, Clark J, Mimnaugh E, Krutzsch H, Ochel HJ, Schulte TW, Sausville E, Neckers LM, Toft DO | title = The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation | journal = J. Biol. Chem. | volume = 272 | issue = 38 | pages = 23843–50 | year = 1997 | month = September | pmid = 9295332 | url = | doi = 10.1074/jbc.272.38.23843 ]

Hsp90, while in the open conformation, leaves some hydrophobic residues exposed, to which unfolded and misfolded proteins that have unusual hydrophobic regions exposed are recruited with high affinity.cite journal | author = Xu Z, Horwich AL, Sigler PB | title = The crystal structure of the asymmetric GroEL-GroES-(ADP)7 chaperonin complex | journal = Nature | volume = 388 | issue = 6644 | pages = 741–50 | year = 1997 | month = August | pmid = 9285585 | doi = 10.1038/41944 | url = | issn = ] When a bound substrate is in place, the energy releasing ATP hydrolysis by the ATPase function near the NTD forces conformational changes which clamps the Hsp90 down onto the substrate. In a reaction similar to that of other molecular clamp proteins like GyrB and MutL, this site drives virtually all of the protein folding functions that Hsp90 plays a role in. In contrast MutL and GyrB function as topoisomerases and use a charge clamp with a high amount of positively charged sidechains that is electrostatically attracted to the negative backbone of DNA.cite journal | author = Kampranis SC, Bates AD, Maxwell A | title = A model for the mechanism of strand passage by DNA gyrase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 15 | pages = 8414–9 | year = 1999 | month = July | pmid = 10411889 | pmc = 17530 | url = | doi = 10.1073/pnas.96.15.8414 ]

The ability of Hsp90 to clamp onto proteins allows it perform several functions including assisting folding, preventing aggregation, and facilitating transport.

Function

Normal cells

In unstressed cells, Hsp90 plays a number of important roles, which include assisting in folding, intracellular transport, maintenance, and degradation of proteins as well as facilitating cell signaling.

Protein folding and chaperone

Hsp90 is known to associate with the non-native structures of many proteins which has lead to the proposal that Hsp90 is involved in protein folding in general.cite journal | author = Buchner J | title = Hsp90 & Co. - a holding for folding | journal = Trends Biochem. Sci. | volume = 24 | issue = 4 | pages = 136–41 | year = 1999 | month = April | pmid = 10322418 | doi = 10.1016/S0968-0004(99)01373-0 | url = | issn = ] Furthermore Hsp90 has been shown to suppress the aggregation of a wide range of "client" or "substrate" proteins and hence acts as a general protective chaperone.cite journal | author = Miyata Y, Yahara I | title = The 90-kDa heat shock protein, Hsp90, binds and protects casein kinase II from self-aggregation and enhances its kinase activity | journal = J. Biol. Chem. | volume = 267 | issue = 10 | pages = 7042–7 | year = 1992 | month = April | pmid = 1551911 | doi = | url = http://www.jbc.org/cgi/content/abstract/267/10/7042 | issn = ] cite journal | author = Wiech H, Buchner J, Zimmermann R, Jakob U | title = Hsp90 chaperones protein folding in vitro | journal = Nature | volume = 358 | issue = 6382 | pages = 169–70 | year = 1992 | month = July | pmid = 1614549 | doi = 10.1038/358169a0 | url = | issn = ] cite journal | author = Jakob U, Lilie H, Meyer I, Buchner J | title = Transient interaction of Hsp90 with early unfolding intermediates of citrate synthase. Implications for heat shock in vivo | journal = J. Biol. Chem. | volume = 270 | issue = 13 | pages = 7288–94 | year = 1995 | month = March | pmid = 7706269 | doi = 10.1074/jbc.270.13.7288 | url = | issn = ] However Hsp90 is somewhat more selective than other chaperones.cite journal | author = Picard D | title = Heat-shock protein 90, a chaperone for folding and regulation | journal = Cell. Mol. Life Sci. | volume = 59 | issue = 10 | pages = 1640–8 | year = 2002 | month = October | pmid = 12475174 | doi = 10.1007/PL00012491 | url = | issn = ]

Protein degradation

Eukaryotic proteins which are no longer needed or are misfolded or otherwise damaged are usually marked for destruction by the polyubiquitation pathway. These ubiquitinated proteins are recognized and degraded by the 26S proteasome.cite journal | author = Imai J, Maruya M, Yashiroda H, Yahara I, Tanaka K | title = The molecular chaperone Hsp90 plays a role in the assembly and maintenance of the 26S proteasome | journal = EMBO J. | volume = 22 | issue = 14 | pages = 3557–67 | year = 2003 | month = July | pmid = 12853471 | pmc = 165619 | doi = 10.1093/emboj/cdg349 | url = ] cite journal | author = Correia MA, Sadeghi S, Mundo-Paredes E | title = Cytochrome P450 ubiquitination: branding for the proteolytic slaughter? | journal = Annu. Rev. Pharmacol. Toxicol. | volume = 45 | issue = | pages = 439–64 | year = 2005 | pmid = 15822184 | doi = 10.1146/annurev.pharmtox.45.120403.100127 | url = ] Hence the 26S proteasome is an integral part of the cell's mechanism to degrade proteins. Furthermore a constant supply of functional Hsp90 needed to maintain the tertiary structure of the proteasome.cite journal | author = Kimura Y, Matsumoto S, Yahara I | title = Temperature-sensitive mutants of hsp82 of the budding yeast Saccharomyces cerevisiae | journal = Mol. Gen. Genet. | volume = 242 | issue = 5 | pages = 517–27 | year = 1994 | month = March | pmid = 8121410 | url = | doi = 10.1007/BF00285275 ] Finally experiments done with heat sensitive Hsp90 mutants and the 26S proteasome suggest that Hsp90 is responsible for most, if not all, of the ATPase activity of the proteasome.

Interaction with steroid receptors

The glucocorticoid receptor (GR) is the most thoroughly studied example of a steroid receptor whose function is crucially dependent on interactions with Hsp90.cite journal | author = Pratt WB, Morishima Y, Murphy M, Harrell M | title = Chaperoning of glucocorticoid receptors | journal = Handb Exp Pharmacol | volume = | issue = 172 | pages = 111–38 | year = 2006 | pmid = 16610357 | doi = 10.1007/3-540-29717-0_5 | url = | issn = ] cite journal | author = Grad I, Picard D | title = The glucocorticoid responses are shaped by molecular chaperones | journal = Mol. Cell. Endocrinol. | volume = 275 | issue = 1-2 | pages = 2–12 | year = 2007 | month = September | pmid = 17628337 | doi = 10.1016/j.mce.2007.05.018 | url = | issn = ] In the absence of the steroid hormone cortisol, GR resides in the cytosol complexed with several chaperone proteins including Hsp90 (see figure to the right). These chaperones maintain the GR in a state capable of binding hormone. A second role of Hsp90 is to bind immunophilins (e.g., FKBP52) that attach the GR complex to the dynein protein trafficking pathway which translocates the activated receptor from the cytoplasm into the nucleus.cite journal | author = Pratt WB, Galigniana MD, Morishima Y, Murphy PJ | title = Role of molecular chaperones in steroid receptor action | journal = Essays Biochem. | volume = 40 | issue = | pages = 41–58 | year = 2004 | pmid = 15242338 | doi = | url = http://essays.biochemistry.org/bsessays/040/bse0400041.htm | issn = ] Once in the nucleus, the GR dimerizes and binds to specific sequences of DNA and thereby upregulates the expression of GR responsive genes. Hsp90 is also required for the proper functioning of several other steroid receptors, including those responsible for the binding of aldosterone,cite journal | author = Rafestin-Oblin ME, Couette B, Radanyi C, Lombes M, Baulieu EE | title = Mineralocorticosteroid receptor of the chick intestine. Oligomeric structure and transformation | journal = J. Biol. Chem. | volume = 264 | issue = 16 | pages = 9304–9 | year = 1989 | month = June | pmid = 2542305 | doi = | url = http://www.jbc.org/cgi/content/abstract/264/16/9304 | issn = ] androgen,cite journal | author =Joab I, Radanyi C, Renoir M, Buchou T, Catelli MG, Binart N, Mester J, Baulieu EE | title = Common non-hormone binding component in non-transformed chick oviduct receptors of four steroid hormones | journal = Nature | volume = 308 | issue = 5962 | pages = 850–3 | year = 1984 | pmid = 6201744 | doi = 10.1038/308850a0 | url = | issn = ] estrogen,cite journal | author = Redeuilh G, Moncharmont B, Secco C, Baulieu EE | title = Subunit composition of the molybdate-stabilized "8-9 S" nontransformed estradiol receptor purified from calf uterus | journal = J. Biol. Chem. | volume = 262 | issue = 15 | pages = 6969–75 | year = 1987 | month = May | pmid = 3584104 | doi = | url = http://www.jbc.org/cgi/content/abstract/262/15/6969 | issn = ] and progesterone.cite journal | author = Catelli MG, Binart N, Jung-Testas I, Renoir JM, Baulieu EE, Feramisco JR, Welch WJ | title = The common 90-kd protein component of non-transformed '8S' steroid receptors is a heat-shock protein | journal = EMBO J. | volume = 4 | issue = 12 | pages = 3131–5 | year = 1985 | month = December | pmid = 2419124 | pmc = 554632 | doi = | url = | issn = ]

Cancerous cells

Cancerous cells over express a number of proteins, including PI3K and AKT and inhibition of these two proteins triggers apoptosis. Furthermore Hsp90 stabilizes the PI3K and AKT proteins. Hence inhibition of Hsp90 appears to induce apoptosis through inhibition of the PI3K/AKT signaling pathway.cite journal | author = Mohsin SK, Weiss HL, Gutierrez MC, Chamness GC, Schiff R, Digiovanna MP, Wang CX, Hilsenbeck SG, Osborne CK, Allred DC, Elledge R, Chang JC | title = Neoadjuvant trastuzumab induces apoptosis in primary breast cancers | journal = J. Clin. Oncol. | volume = 23 | issue = 11 | pages = 2460–8 | year = 2005 | month = April | pmid = 15710948 | doi = 10.1200/JCO.2005.00.661 | url = ] cite journal | author = Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP | title = Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent | journal = Cell | volume = 89 | issue = 2 | pages = 239–50 | year = 1997 | month = April | pmid = 9108479 | url = | doi = 10.1016/S0092-8674(00)80203-2 ]

Another important role of Hsp90 in cancer is the stabilization of mutant proteins such as v-Src, the fusion oncogene Bcr/Abl, and p53 that appear during cell transformation. It appears that Hsp90 can act as a "protector" of less stable proteins produced by DNA mutations.cite journal | author = Calderwood SK, Khaleque MA, Sawyer DB, Ciocca DR | title = Heat shock proteins in cancer: chaperones of tumorigenesis | journal = Trends Biochem. Sci. | volume = 31 | issue = 3 | pages = 164–72 | year = 2006 | month = March | pmid = 16483782 | doi = 10.1016/j.tibs.2006.01.006 | url = ]

Hsp90 is also required for induction of vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS).cite journal | author = Fontana J, Fulton D, Chen Y, Fairchild TA, McCabe TJ, Fujita N, Tsuruo T, Sessa WC | title = Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release | journal = Circ. Res. | volume = 90 | issue = 8 | pages = 866–73 | year = 2002 | month = May | pmid = 11988487 | url = | doi = 10.1161/01.RES.0000016837.26733.BE ] Both are important for "de novo" angiogenesis that is required for tumour growth beyond the limit of diffusion distance of oxygen in tissues. It also promotes the invasion step of metastasis by assisting the matrix metalloproteinase MMP2.cite journal | author = Eustace BK, Sakurai T, Stewart JK, Yimlamai D, Unger C, Zehetmeier C, Lain B, Torella C, Henning SW, Beste G, Scroggins BT, Neckers L, Ilag LL, Jay DG | title = Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness | journal = Nat. Cell Biol. | volume = 6 | issue = 6 | pages = 507–14 | year = 2004 | month = June | pmid = 15146192 | doi = 10.1038/ncb1131 | url = ] Together with its co-chaperones, Hsp90 modulates tumour cell apoptosis "mediated through effects on AKT,cite journal | author = Sato S, Fujita N, Tsuruo T | title = Modulation of Akt kinase activity by binding to Hsp90 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 20 | pages = 10832–7 | year = 2000 | month = September | pmid = 10995457 | pmc = 27109 | doi = 10.1073/pnas.170276797 | url = ] tumor necrosis factor receptors (TNFR) and nuclear factor-κB (NF- κB) function."cite journal | author = Whitesell L, Lindquist SL | title = Hsp90 and the chaperoning of cancer | journal = Nat. Rev. Cancer | volume = 5 | issue = 10 | pages = 761–72 | year = 2005 | month = October | pmid = 16175177 | doi = 10.1038/nrc1716 | url = ] Finally Hsp90 participates in many key processes in oncogenesis such as self-sufficiency in growth signals, stabilization of mutant proteins, angiogenesis, and metastasis.

Targeting Hsp90 with drugs has shown promising effects in clinical trials. For example, the Hsp90 inhibitor, geldanamycin has been used as an anti-tumor agent with great success, 50% reduction of tumor growth has been realized with doses of geldanamycin. ] The drug was originally thought to be a kinase inhibitor. However it has since been shown to be an Hsp90 inhibitor where it uses a compact conformation to insert itself into the ATP binding site.

ummary

It is clear that Hsp90 plays a Janus-like role in the cell, where it is essential for the creation, maintenance, and destruction of proteins. Its normal function is critical to maintaining the health of cells while its dysregulation in contrast may contribute to carcinogenesis. The ability for the chaperone to both make the 26S proteasome stable "in vivo", so as to allow the cell to degrade unwanted and/or harmful proteins in a timely manner and to be responsible for allowing tumor causing kinases to persist in the cytoplasm that would normally be broken down by the same proteasome, confirms these specific roles and at the same time show its functional diversity. Clinical cancer treatment trials, such as those with geldanamycin and its derivatives, have put Hsp90's importance into focus and have highlighted the need for full scale research into Hsp90 related pathways. Combined with the interest in Hsp90's "in vivo" protein folding functions by proteomics researchers, this chaperone will continue to be a research priority for the foreseeable future.

References

External links

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