Molecular Chaperones in Health and Disease PDF
Preview Molecular Chaperones in Health and Disease
Handbook of Experimental Pharmacology Volume 172 Editor-in-Chief K.Starke,Freiburgi.Br. EditorialBoard G.V.R.Born,London M.Eichelbaum,Stuttgart D.Ganten,Berlin F.Hofmann,München W.Rosenthal,Berlin G.Rubanyi,Richmond,CA Molecular Chaperones in Health and Disease Contributors S.Alberti,I.J.Benjamin,M.Brunet,J.Buchner,E.S.Christians, P.Csermely,C.Didelot,F.Edlich,J.G.Facciponte,G.Fischer, M.Gaestel,C.Garrido,J.M.Harrell,J.Höhfeld,I.Judson, H.H.Kampinga,R.J.Kaufman,M.Morange,Y.Morishima, G.Multhoff,P.J.M.Murphy,L.Neckers,E.Papp,W.B.Pratt, T.Scheibel,C.Soti,J.R.Subjeck,J.Tatzelt,R.Voellmy, X.-Y.Wang,K.F.Winklhofer,P.Workman,K.Zhang Editor Matthias Gaestel 123 Professor MatthiasGaestel MedicalSchoolHannover InstituteofBiochemistry Carl-Neuberg-Str.1 30625Hannover Germany [email protected] With36Figuresand20Tables ISSN 0171-2004 ISBN-10 3-540-25875-2 SpringerBerlinHeidelbergNewYork ISBN-13 978-3-540-25875-9 SpringerBerlinHeidelbergNewYork LibraryofCongressControlNumber:2005925882 Thisworkissubjecttocopyright.Allrightsreserved,whetherthewholeorpartofthematerialis concerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broad- casting,reproductiononmicrofilmorinanyotherway,andstorageindatabanks.Duplicationof thispublicationorpartsthereofispermittedonlyundertheprovisionsoftheGermanCopyrightLaw ofSeptember9,1965,initscurrentversion,andpermissionforusemustalwaysbeobtainedfrom Springer.ViolationsareliableforprosecutionundertheGermanCopyrightLaw. SpringerisapartofSpringerScience+BusinessMedia springeronline.com ©Springer-VerlagBerlinHeidelberg2006 PrintedinGermany Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispublicationdoesnot imply, even in theabsence of a specific statement, thatsuchnames are exempt from the relevant protectivelawsandregulationsandthereforefreeforgeneraluse. Productliability:Thepublisherscannotguaranteetheaccuracyofanyinformationaboutdosageand applicationcontainedinthisbook.Ineveryindividualcasetheusermustchecksuchinformationby consultingtherelevantliterature. Editor:S.Rallison EditorialAssistant:S.Dathe Coverdesign:design&productionGmbH,Heidelberg,Germany Typesettingandproduction:LE-TEXJelonek,Schmidt&VöcklerGbR,Leipzig,Germany Printedonacid-freepaper 27/3151-YL-543210 Preface Morethan40yearsafterFerruccioRitossas’sdiscoveryofheatshock-induced formationofpuffsinthepolytenechromosomesofDrosophila,manydifferent familiesofheatshockproteinsandmolecularchaperoneshaveemergedand havebeencontinuouslystudiedinstructureandfunctionuntiltoday.Asare- sult,ithasnowbecomeclearthatmolecularchaperonesareinvolvedinawide varietyofessentialprocessesinlivingcells.Molecularchaperonesnotonlypro- tectcellsfromstressdamagebykeepingcellularproteinsinafoldingcompetent stateandpreventingthemfromirreversibleaggregation,buttheyarealsoex- pressedconstitutivelyinthecellandparticipateincomplexprocessessuchas proteinsynthesis,intracellularproteintransport,post-translationalmodifica- tion,andsecretionofproteinsaswellasreceptorsignaling.Hence,itisnotsur- prisingthatmolecularchaperonesareimplicatedinthepathogenesisofmany relevantdiseasesandcouldberegardedaspotentialpharmacologicaltargets. Startingwiththeanalysisofthemodeofactionofchaperonesandtheregu- lationoftheheatshockresponseatthemolecular,cellular,andorganismlevel, this book then focuses on specific aspects, such as signal transduction, de- velopment,apoptosis,proteinaggregationinvivo,oncogenictransformation, and immune response, where chaperones play a crucial role. Modulation of chaperoneactionandtheuseofso-calledsmall-moleculechaperonesisclearly ofpharmacologicalinterestandcouldbeoftherapeuticrelevanceforthetreat- mentofdiseasesthatresultfromderegulationoftheabove-mentionedcellular processesinwhichchaperonesareinvolved.Thechaptersofthethirdandlast part of this volume critically analyze this potential and illustrate significant progressintherapeuticapplication. I am delighted that so many experts in the different areas of chaperone research contributed to this volume and I want to thank them for providing high-quality chapters in time to meet the publisher’s deadline and ensure publication of this exciting volume in 2005. I want to acknowledge the very effective and professional support from Mrs. Susanne Dathe at Springer. I hope that this volume will give a balanced overview as well as specific and detailedinformationonmostofthetopicsofinterestforbothspecialistsinthe fieldandnewcomersinvolvedinexperimentalandtherapeuticapproachesof pharmacologicalmodulationofheatshockresponseandchaperoneaction. Hannover,May2005 MatthiasGaestel ListofContents ChaperonesinPreventingProteinDenaturationinLivingCells andProtectingAgainstCellularStress. . . . . . . . . . . . . . . . . . . 1 H.H.Kampinga FeedbackRegulationoftheHeatShockResponse . . . . . . . . . . . . 43 R.Voellmy ProteinFoldingintheEndoplasmicReticulum andtheUnfoldedProteinResponse . . . . . . . . . . . . . . . . . . . . 69 K.Zhang,R.J.Kaufman MolecularChaperonesinSignalTransduction . . . . . . . . . . . . . . 93 M.Gaestel ChaperoningofGlucocorticoidReceptors . . . . . . . . . . . . . . . . 111 W.B.Pratt,Y.Morishima,M.Murphy,M.Harrell HeatShockResponse:LessonsfromMouseKnockouts . . . . . . . . . 139 E.S.Christians,I.J.Benjamin HSFsinDevelopment . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 M.Morange HeatShockProteins:EndogenousModulatorsofApoptoticCellDeath . 171 C.Didelot,E.Schmitt,M.Brunet,L.Maingret,A.Parcellier,C.Garrido ProteinAggregationasaCauseforDisease . . . . . . . . . . . . . . . . 199 T.Scheibel,J.Buchner TheRoleofChaperonesinParkinson’sDiseaseandPrionDiseases . . . 221 K.F.Winklhofer,J.Tatzelt ChaperoningOncogenes:Hsp90asaTargetofGeldanamycin . . . . . . 259 L.Neckers HeatShockProteinsinImmunity . . . . . . . . . . . . . . . . . . . . . 279 G.Multhoff VIII ListofContents MolecularChaperonesandCancerImmunotherapy . . . . . . . . . . . 305 X.-Y.Wang,J.G.Facciponte,J.R.Subjeck Hsp90InhibitorsintheClinic . . . . . . . . . . . . . . . . . . . . . . . 331 S.Pacey,U.Banerji,I.Judson,P.Workman PharmacologicalTargetingofCatalyzedProteinFolding: TheExampleofPeptideBondcis/transIsomerases . . . . . . . . . . . . 359 F.Edlich,G.Fischer ChemicalChaperones:MechanismsofActionandPotentialUse . . . . 405 E.Papp,P.Csermely PharmacologicalModulationoftheHeatShockResponse . . . . . . . . 417 C.So˝ti,P.Csermely SubjectIndex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437 ListofContributors (Addressesstatedatthebeginningofrespectivechapters) Banerji,U.,331 Morishima,Y.,111 Benjamin,I.J.,139 Multhoff,G.,279 Brunet,M.,171 Murphy,M.,111 Buchner,J.,199 Neckers,L.,259 Christians,E.S.,139 Csermely,P.,405,417 Pacey,S.,331 Papp,E.,405 Didelot,C.,171 Parcellier,A.,171 Pratt,W.B.,111 Edlich,F.,359 Facciponte,J.G.,305 So˝ti,C.,417 Fischer,G.,359 Scheibel,T.,199 Schmitt,E.,171 Gaestel,M.,93 Subjeck,J.R.,305 Garrido,C.,171 Tatzelt,Jörg,221 Harrell,M.,111 Voellmy,R.,43 Judson,I.,331 Wang,X.-Y.,305 Kampinga,H.H.,1 Winklhofer,K.F.,221 Kaufman,R.J.,69 Workman,P.,331 Maingret,L.,171 Morange,M.,153 Zhang,K.,69 HEP(2006)172:1–42 ©Springer-VerlagBerlinHeidelberg2006 ChaperonesinPreventingProteinDenaturation inLivingCellsandProtectingAgainstCellularStress H.H.Kampinga DepartmentofCellBiology,SectionofRadiationandStressCellBiology, FacultyofMedicalSciences,UniversityofGroningen,Ant.Deusinglaan1, 9713AVGroningen,TheNetherlands [email protected] 1 TheMolecularChaperoneConcept . . . . . . . . . . . . . . . . . . . . . . . . 2 2 ScopeofThisChapter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3 TheHsp70GeneFamily . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.1 RegulationoftheMammalianHsp70ATP/ADPCycle . . . . . . . . . . . . . . 7 3.1.1 TheHdjFamily . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.1.2 Hip . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.1.3 TheBagFamily . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.1.4 CHIP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.1.5 OtherPossibleRegulatorsoftheHsp70ChaperoneMachine . . . . . . . . . . 11 3.2 Hsp70-Hsp90ConnectionsandHopandTpr-2Co-factors . . . . . . . . . . . 12 3.3 Hsp70-Hsp27Connections . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 4 InternalandExternalProteotoxicStressesinMammalianCells . . . . . . . . 13 5 ThermotoleranceandHspReallocationsinMammalianCells . . . . . . . . . 14 6 ModelsSystemsforStudyingHspChaperone-LikeActivities inStressedLivingMammalianCells . . . . . . . . . . . . . . . . . . . . . . . 16 6.1 EffectsofHspAgainstEffectsofHeatonCellularStructuresandFunctions . . 16 6.2 HspExpressionandEndogenousReporterProteins. . . . . . . . . . . . . . . 17 6.3 HspExpressionandExogenousReporterProteins . . . . . . . . . . . . . . . 17 6.3.1 Hsp70andHsp40 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 6.3.2 Hsp70andHip . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 6.3.3 Hsp70andBag-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 6.3.4 Hsp70andCHIP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 6.3.5 ChaperoneNetworks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 7 FateofProteins:FoldingorDegradation? . . . . . . . . . . . . . . . . . . . . 23 8 ProteotoxicDamage:CellularTargets,Sorting,andHsp-MediatedProtection 24 8.1 ProcessingofDamagedProteinsintheCytosol . . . . . . . . . . . . . . . . . 25 8.2 ProcessingofDamagedProteinsintheNucleus . . . . . . . . . . . . . . . . . 26 9 CellDeathExpression,CellTransformationandHsp . . . . . . . . . . . . . . 27 10 ConcludingRemarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 2 H.H.Kampinga Abstract A variety of cellular internal andexternal stress conditionscan beclassified as proteotoxicstresses.Proteotoxicstressescanbedefinedasstressesthatincreasethefraction ofproteinsthatareinanunfoldedstate,therebyenhancingtheprobabilityoftheformation of intracellular aggregates. These aggregates, if not disposed, can lead to cell death. In responsetotheappearanceofdamagedproteins,cellsinducetheexpressionofheatshock proteins.Thesecanfunctionasmolecularchaperonestopreventproteinaggregationand tokeepproteinsinastatecompetentforeitherrefoldingordegradation.Mostknowledge ofthefunctionandregulation(byco-factors)ofindividualheatshockproteinscomesfrom cellfreestudiesonrefoldingofheat-orchemicallydenatured,purifiedproteins.Unlikethe experimentalsituationinatesttube,cellscontainmultiplechaperonesandco-factorsoften movinginandoutdifferentsubcompartmentsthatcontainavarietyofproteinsubstratesat differentfoldingstates.Also,withincellsfoldingcompeteswiththedegradativemachinery. Inthischapter,anoverviewwillbeprovidedonhowthemaincytosolic/nuclearchaperone Hsp70isregulated,whatisknownaboutitsinteractionwithothermaincytosolic/nuclear chaperonefamilies(Hsp27,Hsp90,andHsp110),andhowitmayfunctionasamolecular chaperoneinlivingmammaliancellstoprotectagainstproteotoxicstresses. Keywords Chaperones·Mammaliancells·Hsp70·Proteotoxicstress 1 TheMolecularChaperoneConcept Thesuccessfulinvitro(cell-freesystem)foldingofpurifiedribonucleaseAby Anfinsen(Anfinsen1973)ledtothesuggestionthatallinformationnecessary forapolypeptidetofoldwasanintrinsicfeatureofitsprimarystructureand wasindependentofotherfactors(EllisandHemmingsen1989).Mostofthese refoldingexperimentswereperformedbyfirstdenaturingapurifiedpolypep- tide with chemical agents and then removing the denaturant. The probabil- ity that such a polypeptidewill fold correctly after removing the denaturant increases at low protein concentration (which limits interpolypeptide inter- actions) and low temperatures (which attenuates hydrophobic interactions). Thehighproteinconcentrationsandtemperatureswithinthecellleadtopre- matureinteractionsofnewlysynthesizedpolypeptides,oftenaccompaniedby misfolding and aggregation (Jaenicke 1991). To assist polypeptidefolding in vivo,asetofproteins,calledmolecularchaperones,existwhosefunctionisto ensure that polypeptides will either fold or be transported properly. In bio- chemicalterms,amolecularchaperoneisdefinedas“aproteinthatprevents improper interactions between potentially complementary surfaces and dis- ruptsanyimproperliaisonsthatmayoccur”(EllisandHemmingsen1989).The proposedfunctionofchaperonesistoassistinself-assemblyofproteinsbyin- hibitingalternativeassemblypathwaysthatproducenonfunctionalstructures. Itisimportanttonotethatachaperoneactivitymerelypreventsaggregation anddoesnotnecessarilyneedtobeassociatedwith(re)foldingofthebound substrate. StresProtectionbyChaperonesinCells 3 Mostofourknowledgeonthefunctionandregulationofmolecularchap- erones and interactions between the main chaperone machines comes from cell-free experiments in which model proteins are either chemicallyor ther- mallydenaturedintheabsenceandpresenceofproposedchaperones(Buchner etal.1991;Jakobetal.1993;Knaufetal.1994;Martinetal.1993;Skowyraetal. 1990;Wiechetal.1992).Aggregationofthepolypeptidescanbemeasuredby lightscatteringandrefoldingtothenativestatebymeasuringtheactivityof thepolypeptides.Thesestudieshaverevealedthatthemammalianheatshock proteinsHsp27,Hsp60,Hsp70,Hsp90,andHsp110canholdunfoldedmodel substratesinarefoldableconformationduringstressconditions.Subsequent refoldingoftheunfoldedproteinsrequirestheactivitiesoftheHsp70chaper- onemachine(Buchner1996;Ehrnspergeretal.1997;FreemanandMorimoto 1996;Jakobetal.1993;Schneideretal.1996;Wiechetal.1992).Thisiswhythe Hsp70 chaperone machine is the most widely studied one in relation to cel- lularstressesandwhythischapterwillemphasizeonthismachine.However, someHsp70interactionswithHsp27,Hsp90,orHsp110willalsobediscussed because they are relevant for the protective action of Hsp70 against cellular stresses. 2 ScopeofThisChapter Unliketheexperimentalsituation ina testtube,cellscontain multiplechap- erones in different (sub)compartmentsto whichtheyoften canmove inand out dynamically and in which other macromolecules—protein substrates at differentfoldingstates,adegradativemachinery,andavarietyofco-factors— are present, which will influence the activities of the heat shock proteins. At thesametime,whencellsareexposedtoexternalstressessuchasheatshock, energyisabsorbedthroughoutthecell,damagingnearlyallclassesofmacro- moleculesandaffectingmanycellularstructuresandfunctions.Thischapter providesanoverviewofthecytoprotectivechaperonefunctionsofheatshock proteinsreflectedinthiscomplexenvironmentofalivingcell.Todoso,first a short overview will be provided on the data obtained with cell-free sys- temsregardingtheregulationoftheHsp70chaperonemachine,asthesehave providedabasisandatoolboxfortheworkinlivingmammaliancells. 3 TheHsp70GeneFamily Proteins encoded by the Hsp70 gene family are highly conserved and found in all organisms, from bacteria to humans. In prokaryotes, 3 Hsp70 family members—DnaK, Hsc66 and Hsc62—exist (Itoh et al. 1999). Most of our
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