Reviews of Physiology, Biochemistry and Pharmacology

92 Pages·2006·4.05 MB·English

by  E. A. Craig, P. Huang, R. Aron, A. Andrew (auth.), S.G. Amara, E. Bamberg, S. Grinstein, S.C. Hebert, R. Jahn, W.J. Lederer, R. Lill, A. Miyajima, H. Murer, S. Offermanns, G. Schultz, M. Schweiger (eds.)

ReviewsofPhysiology,BiochemistryandPharmacology156
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156 Physiology
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RevPhysiolBiochemPharmacol(2006)
DOI10.1007/s10254-005-0001-0
E.A.Craig·P.Huang·R.Aron·A.Andrew
The diverse roles of J-proteins, the obligate Hsp70 co-chaperone
Publishedonline:20January2006
©Springer-Verlag2006
Abstract Hsp70s and J-proteins, which constitute one of the most ubiquitous types of
molecularchaperonemachineries,functioninawidevarietyofcellularprocesses.J-proteins
playacentralrolebystimulatinganHsp70’sATPaseactivity,therebystabilizingitsinter-
actionwithclientproteins.However,whileallJ-proteinsservethiscorepurpose,individual
proteinsarebothstructurallyandfunctionallydiverse.Some,butnotall,J-proteinsinteract
withclientpolypeptidesthemselves,facilitatingtheirbindingtoanHsp70.SomeJ-proteins
havemanyclientproteins,othersonlyone.CertainJ-proteins,whilenotothers,aretethered
toparticularlocationswithinacellularcompartment,thus“recruiting”Hsp70stothevicin-
ityoftheirclients.HerewereviewrecentworkonthediversefamilyofJ-proteins,outlining
emergingthemesconcerningtheirfunction.
Introductoryremarks
Molecular chaperones are a ubiquitous class of proteins that interact with short stretches
ofhydrophobicaminoacidstypicallyexposedinpartiallyunfoldedproteins.Throughsuch
interactions, chaperones function in a broad range of physiological processes, facilitating
proteinfolding,proteintranslocationacrossmembranes,andremodelingofmultimericpro-
teincomplexes.Hsp70sandJ-proteins(oftenalsoreferredtocollectivelyasDnaJ-likepro-
teins or Hsp40s), which form obligate partnerships, areamong themost ubiquitous of the
chaperones.Infact,mosteukaryoticandprokaryoticgenomesencodebothmultipleHsp70s
andmultipleJ-proteins,reflectingthefactthattheyhaveevolvedtofunctioninsuchawide
variety of processes. The number of J-proteins, particularly, has expanded with the com-
E.A.Craig((cid:1))·P.Huang·R.Aron·A.Andrew
UniversityofWisconsin-Madison,441EBiochemistryAddition,DepartmentofBiochemistry,
433BabcockDrive,Madison,53706WI,USA
e-mail:[email protected]·Tel.:[phone]·Fax:[phone]
R.Aron·A.Andrew
UniversityofWisconsin-Madison,GraduatePrograminBiomolecularChemistry,
Madison,53706WI,USA
2 RevPhysiolBiochemPharmacol(2006)
plexityoftheorganisminwhichtheyarefound.Forexample,theEscherichiacoligenome
has6J-proteins, theyeastSaccharomyces cerevisiaegenome, 22,andthehuman genome,
approximately32.
Over the years most research has focused on the Hsp70 component of this chaperone
machinery (Bukau and Horwich 1998; Erbse et al. 2004; Slepenkov and Witt 2002). The
structure and amino acid sequence of Hsp70s from different organisms and different or-
ganellesareremarkablysimilar.AllarecomposedofahighlyconservedN-terminalATPase
domain, followedbyaless-conservedpeptide-binding domain having acleft inwhichhy-
drophobic stretchesofapproximately fiveamino acids interact. Bindingand hydrolysis of
ATPintheN-terminusregulatestheinteractionoftheC-terminuswithunfoldedorpartially
unfoldedclientpolypeptides.ATPhydrolysisstabilizestheinteractionwiththesepolypep-
tidesubstrates. Theessenceof allJ-protein function is theabilitytostimulatetheATPase
activity of Hsp70 upon the transient interaction of their highly conserved J-domains with
Hsp70’sATPasedomain.
Inthisreview,meanttocomplementearlierreviewsthatalsofocusedonJ-proteinfunc-
tion (Cheethamand Caplan1998; Fanet al.2003; Walshet al.2004), wefirstdiscuss the
J-domain that is obligatory for the in vivo function of all J-proteins. However, since all
J-proteinshavedomainsinadditiontotheirJ-domain,theremainderofthereviewconcen-
trates on recent work aimed at understanding the diverse roles played by these different
regions. Some,but notall,ofthesedomains bindclientproteins whosetransfertoHsp70s
is facilitated by the J-domain. Other domains of J-proteins serve to target the J-protein to
aparticularlocationwithinthecellularcompartmentinwhichtheyfunction.Belowweout-
line what is known about theseadditional domains, focusing on theyeast S. cerevisiae as
amodelbecauseoftheavailabilityofextensivegenomicandgeneticanalyses.
TheJ-domain:thecommondenominator
J-proteins,bydefinition,containaconserved, roughly 70-amino-acid signatureregion, the
J-domain, namedafterthewell-studiedE.coliprotein, DnaJ.TheDnaJJ-domaincontains
four α helices, with helices II and III forming a coiled-coil motif around a hydrophobic
core(Pellecchiaetal.1996;Fig.1a).TheJ-domainsoftwomammalianJ-proteins,human
Hdj1(Qianetal.1996)andmurinepolyomavirustumorantigen(Berjanskiietal.2000),are
remarkably similar. Even the more divergent auxilin J-domain possesses these conserved
J-domainfeatures,whilealsohavinganN-terminalhelixandalongloopinsertedbetween
helicesIandII(Jiangetal.2003).
The most highly conserved amino acids of J-domains, the histidine-proline-aspartate
(HPD)tripeptidelocatedintheloopbetweenhelixIIandIII,hasbeenshowntobecritical
for ATPasestimulationinmany systems,and thus invivo function (Feldheim et al. 1992;
TsaiandDouglas1996;Voisineetal.2001;Walletal.1994;Yanetal.1998).However,ad-
ditionalresidues,bothwithinhelicesIIandIIIandwithintheinterveningloop,arerequired
fortheinvivofunctionofDnaJ(Genevauxetal.2002).Thesidechainsoftheseresiduesand
thoseoftheHPDtripeptidearesolvent-exposedandorientedinthesamedirection,andthus
possibly form an Hsp70 interaction surface. Indeed, nuclear magnetic resonance (NMR)
perturbation mapping of the J-domain of DnaJ in the presence of DnaK indicated a simi-
lar negatively charged surface around helix II as the region involved in DnaK interaction
(Greeneetal.1998;Fig.1b).
RevPhysiolBiochemPharmacol(2006) 3
Fig.1a,b Theinteraction betweentheJ-domainandtheHsp70ATPasedomain.Ribbondiagram(a)and
surface map(b)ofthe J-domain ofDnaJ (PDBfile: 1XBL)(Pellecchia et al. 1996), onthe left, and the
ATPasedomainofDnaK (PDBfile:1DKG)(Harrison etal.1997), ontheright. Basedonthestudies of
DnaK–DnaJ(Genevauxetal.2002;Greeneetal.1998;Gässleretal.1998;Suhetal.1998)andSsb-Zuo1
systems(Huangetal.2005),theresidues(oranalogousresiduesinthecaseoftheSsb-Zuo1system)found
tobeimportant fortheinteraction between aJ-domainandanATPasedomain arehighlighted inorange
withthemostcriticalHPDtripeptidehighlightedinred.ThestructuresarepreparedusingPyMOLsoftware
(http://pymol.sourceforge.net/). HighlightedresiduesinDnaKincludeR167,I169,N170,andT215(Suhet
al.1998);Y145,N147,D148,E217,andV218(Gässleretal.1998),andanalogousresiduesR76,P113,I168,
N170,V192,andF200(Huangetal.2005),allofwhichwereisolatedfromgeneticmutagenesisstudies.The
residueshighlightedinDnaJincludeY25,R26,H33,P34,D35,R36,N37,F47(underlinedistheHPDmo-
tif),fromthemutagenesisstudy(Genevauxetal.2002);andV12,S13,R19,E20,R22,A24,Y25,K26,R27,
L28,M30,Y32,H33,D35,Y54,andT58thatshowedashiftgreater than10HzinNMRanalysis when
DnaKwaspresent(Greeneetal.1998)
ConsistentwithitsabilitytostimulateHsp70’s ATPaseactivity,theJ-domain ofDnaJ
interacts with the ATPasedomain of DnaK in the presence of ATP (Wittung-Stafshede et
al.2003). However,asisthecasewithmostJ-domain:Hsp70 interactions,thisassociation
isquitetransient(Misselwitzetal.1999;Suhetal.1999).Althoughtheexactcontactsites
between any J-protein and Hsp70 are not known, a region of Hsp70 has been implicated
in J-domain interaction in studies of E. coli and S. cerevisiae. Allele-specific suppressors
of the phenotype of dnaJ-D35N, which encodes an alteration of the HPD signature motif
initsJ-domain,wereidentifiedindnaK.Threesuppressorsencoding alterationsinsubdo-
mainIAofDnaK’sATPasedomainwereisolated(Suhetal.1998). Inasimilarapproach,
suppressors ofamutationinZUO1(zuo1-H128Q), whichencodes theJ-proteinpartnerof
Ssb,theyeastribosomeassociatedHsp70,wereisolated.Again,alterationswereclustered
in the AI subdomain (Huang et al. 2005). In addition, site-directed dnaK mutant proteins
havingaminoacidalterationsinthisregionwerefoundtohavedefectsinDnaJinteraction
(Gässleretal.1998). Collectively,theseresiduesformasurfaceontheATPasedomainof
Hsp70(Fig.1b)withagroovenearthenucleotidebindingcleft,makingiteasytoenvision
bindingofaJ-domaincausingstimulationofATPhydrolysisbyHsp70.
4 RevPhysiolBiochemPharmacol(2006)
J-proteinsingeneralproteinfolding:classIandII
DnaJwasthefirstJ-proteinidentifiedandanalyzedandstillservesasastandardtowhich
other J-proteins are compared. Analysis of its sequence led to the grouping of other J-
proteins that containedaglycine-rich andcysteine-richregionadjacent totheJ-domain as
classIJ-proteins,andthosethathadaglycine-richregion,butlackedthecysteine-richregion
asclassII(CheethamandCaplan1998).Thisdefinitionwasbasedonobvioussequencesim-
ilarities,withlittleunderstanding ofthefunctionoftheglycine-andcysteine-richregions.
BelowwediscussthecurrentstateofunderstandingoftheroleofthesedomainsinJ-protein
function.RecentdataalsosuggestthatatleastsomeJ-proteinsgroupedasclassIandIIhave
averysimilarclientprotein-binding domain,aseventhoughverylowinsequenceconser-
vation, they possess a very similar fold. This fold may be common to J-proteins that are
involvedingeneralproteinfoldingwithinthecell,andthusinteractwithawidevarietyof
clientpolypeptides.
Substratebinding:acommonfoldforgeneralproteinfolding?
J-proteins,withtheirHsp70partners,areinvolvedingeneralfoldingofbothnewlysynthe-
sizedandpartiallyunfolded proteins.Evidence existsforsuchageneral functionnot only
forDnaJworking withDnaKintheE.colicytosol,but alsoforJ-proteins inseveralcom-
partments of eukaryotic cells.For example, Ydj1 and Sis1of the yeast cytosol work with
theSsaHsp70s(Aronetal.2005; Kimetal.1998; LuandCyr1998a); Mdj1ofthemito-
chondrialmatrixworkswiththemajorHsp70,Ssc1(Hermannetal.1994;Krzewskaetal.
2001;Rowleyetal.1994);Scj1ofthelumenoftheendoplasmicreticulumworkswithKar2
(Schlenstedt etal.1995; Silbersteinetal.1998). Consistentwithageneral protein-folding
role,Ydj1,Sis1,andMdj1,incooperationwiththeirHsp70partner,arecompetenttofacil-
itaterefoldingofdenaturedsubstratessuchasluciferaseinvitro.Orthologsofeachofthese
yeastproteinsexistinhighereukaryotes,suggestingthatrolesinproteinfoldinghavebeen
conserved, although as discussedthroughout this article, significant functional differences
existamongdifferentJ-proteins.
Recently the structure of the 25-kDa and 19-kDa C-terminal regions of the class I
Ydj1 and class II Sis1 J-proteins, respectively, have been determined (Li et al. 2003; Sha
et al. 2000). Although having very limited sequence similarity, the two fragments are
remarkably alike in structure. Each contains two domains formed by a sandwich of two
β-sheets and a short α-helix, the second of which is followed by sequences important for
dimerization (Fig. 2a). Ydj1 was co-crystallized with the peptide GWLYEIS bound in
ashallowhydrophobic groove intheN-terminal β-sheet domain(domain I).Sis1contains
a hydrophobic groove at the analogous position in the structure that had been predicted
to be the substrate-binding site prior to the determination of the Ydj1 structure (Sha et
al. 2000). Despite the similarities between the adjacent β-sheet domains, it is argued
that the more C-terminal one is not involved in interaction with client proteins, in part
because in the crystal structure the hydrophobic groove of this domain is occupied by
a residue from an adjacent β-strand, and thus not available for interactions with client
proteins.
RevPhysiolBiochemPharmacol(2006) 5
Fig.2a–cStructuralcomparisonofthesubstratebindingdomainsofdifferentJ-proteins.aRibbondiagrams
oftheC-terminalregionsofyeastYdj1(PDBfile:1NLT)(Lietal.2003),Sis1(PDBfile:1C3G)(Shaetal.
2000),andfull-lengthE.coliHscB(PDBfile:1FPO)(Cupp-VickeryandVickery2000)preparedinPyMOL
(http://pymol.sourceforge.net/).ThecrystalstructureofYdj1containstheboundsubstratepeptidehighlighted
inred.Theproposedsubstratebindingdomainsofalltheproteinsareindicatedwiththeyellowbrackets.The
dashedbluebracketindicatesYdj1’scysteine-richregion;thedashedorangebracketindicatestheJ-domain
ofHscB.TheC-terminalend(C)oftheshownstructuresofYdj1andSis1areimmediatelyadjacenttotheir
dimerizationdomainsthatarenotshown.bThelow-resolutionsmall-angleX-rayscattering(SAXS)mod-
elsofmonomeric(left)anddimeric(right)humanDjA1,theclassIJ-proteinorthologofyeastYdj1.The
cysteine-richdomainindicatedbythearrowcanhavedifferentanglestowardstheotherdomainsasshownby
theasymmetricpackinginthedimer.cThelow-resolutionSAXSmodelofdimerichumanDjB4,theclassII
J-proteinorthologofyeastSis1(bandcarereprintedfromBorgesetal.2005).J-domainshighlightedinred,
theanalogoussubstratebindingdomainindicatedwithbracketsandglycine-richregionsindicatedbydashed
lines.(RepublishedwithpermissionofTheJournalofBiologicalChemistry)
6 RevPhysiolBiochemPharmacol(2006)
Fig.3RibbondiagramoftheCys-richdomainsofDnaJ(PDBfile:1EXK)(Martinez-Yamout etal.2000)
andYdj1(PDBfile:1NLT)(Lietal.2003).Thecysteine-richdomainsofDnaJandYdj1containtwozinc
centers.Coordinatedzincatomsarehighlighted inred.Thecysteineresiduesinvolvedinthecoordination
withthezincatomsarehighlightedingreen
Thecysteine-richzinccenter,glycine-rich,anddimerizationdomains
While Sis1and Ydj1 show structural similarity, they alsodiffer significantly. Ydj1 has an
additional subdomain containing two zinc centers that protrudes from domain I of the C-
terminus (Lietal.2003), suchthatitispredictedtoproject intothecleftbetweenthetwo
subunits(Wuetal.2005)(Figs.2and3).Thiscysteine-richdomain,whichisalsopresentin
Scj1andMdj1,aswellasDnaJ,isthedefiningfeature,alongwithaglycine-richregionde-
scribedbelow,ofJ-proteinsclassifiedastypeI(CheethamandCaplan1998).Inallofthese
proteins, this region includes four repeats of CXXCXGXG,suggesting a similar fold. In-
deed,thestructureoftheDnaJsubdomainisverysimilartothatofYdj1(Martinez-Yamout
etal.2000).Inbothcases,twocentersareformed,withrepeats1and4,andrepeats2and
3,eachcoordinatingazincion,formingcenterIandcenterII,respectively(Fig.3).
Themostquantitativeandthoroughanalysisoftheimportanceofthecysteine-richzinc
binding domains has been carried out with DnaJ (Linke et al. 2003), leading to the view
thatthesezinccentersplaydifferent roles:centerIinbindingtoclientproteinsandcenter
IIinfacilitatingtheassociationofclientproteinswithDnaK.DisruptionofcenterIbysub-
stitutionofcysteinesbyserinesdramaticallyaffectedbindingtoaclientprotein,denatured
luciferase,buthadlittleeffectoninvivofunction. DisruptionofcenterIIdidnotsubstan-
tiallyaffectluciferasebinding orstimulationofDnaK’sATPaseactivity,but haddramatic
effectsontheabilityofDnaKtobindluciferaseandwascriticalforinvivofunction.Sim-
ilarly, inYdj1,centerIIwas moreimportant invivo thancenterI, especiallyfor substrate
transfertoHsp70(Fanetal.2005).
Whilethefunction(s)ofthecysteine-richregionisbecomingclearer,thatoftheglycine-
richregion isstillenigmatic, eventhough itspresenceisrequired for classificationofaJ-
proteinasamemberofclassIorII.Typicallytheglycine-richregionalsohasapreponder-
anceofphenylalanineresiduesandthusoftenreferredtoastheG/Fregion.AlltheJ-proteins
discussedabovecontainG/Fregions.NMRstudiesdemonstratethattheG/FregionofDnaJ
(Huang et al. 1999) is very flexible, capable of occupying many different conformational
states.However,itdoesnotsimplyserveasaflexiblelinkerbecause,asdescribedbelow,it
canincludeimportantdeterminantsinthespecificityoffunctionofcertainJ-proteins.
Both Ydj1 and Sis1 are dimers, and in both cases the extreme C-termini are critical
for interaction. In thecaseof Sis1, dimerization occurs via hydrophobic interactions (Sha