The chaperone heat shock protein 70 (Hsp70) and its network of co-chaperones serve as a central hub of cellular protein quality control mechanisms. Domain organization in Hsp70 dictates ATPase activity, ATP dependent allosteric regulation, client/substrate binding and release, and interactions with co-chaperones. The protein quality control activities of Hsp70 are classified as foldase, holdase, and disaggregase activities. Co-chaperones directly assisting protein refolding included J domain proteins and nucleotide exchange factors. However, co-chaperones can also be grouped and explored based on which domain of Hsp70 they interact. Here we discuss how the network of cytosolic co-chaperones for Hsp70 contributes to the functions of Hsp70 while closely looking at their structural features. Comparison of domain organization and the structures of co-chaperones enables greater understanding of the interactions, mechanisms of action, and roles played in protein quality control.
Morán LuengoTMayerMPRüdigerSGD.The Hsp70–Hsp90 chaperone Cascade in protein folding. Trends Cell Biol2019;
29:164–77
2.
CaplanAJ.What is a co-chaperone?Cell Stress Chaper2003;
8:105–7
3.
XuXSarbengEBVorvisCKumarDPZhouLLiuQ.Unique peptide substrate binding properties of 110-kDa heat-shock protein (Hsp110) determine its distinct chaperone activity. J Biol Chem2012;
287:5661–72
4.
GethingM-J.Molecular chaperones: individualists or groupies?Curr Opin Cell Biol1991;
3:610–4
5.
CraigEAGrossCA.Is hsp70 the cellular thermometer. Trends Biochem Sci1991;
16:135–40
6.
QuBJiaYLiuYWangHRenGWangH.The detection and role of heat shock protein 70 in various nondisease conditions and disease conditions: a literature review. Cell Stress Chaperones2015;
20:885–92
7.
FaustORosenzweigR.Structural and biochemical properties of Hsp40/Hsp70 chaperone system. Adv Exp Med Biol2020;
1243:3–20
8.
Fernández-FernándezMRGrageraMOchoa-IbarrolaLQuintana-GallardoLValpuestaJM.Hsp70 – a master regulator in protein degradation. FEBS Lett2017;
591:2648–60
9.
SaibilHR.Chaperone machines in action. Curr Opin Struct Biol2008;
18:35–42
10.
MayerMPBukauB.Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci2005;
62:670–84
11.
Craig EA. Hsp70 at the membrane: driving protein translocation. BMC Biol2018;
16:11
12.
FrydmanJ.Folding of newly translated proteins in vivo: the role of molecular chaperones. Annu Rev Biochem2001;
70:603–48
13.
SchlechtRErbseAHBukauBMayerMP.Mechanics of Hsp70 chaperones enables differential interaction with client proteins. Nat Struct Mol Biol2011;
18:345–51
14.
MayerMPGieraschLM.Recent advances in the structural and mechanistic aspects of Hsp70 molecular chaperones. J Biol Chem2019;
294:2085–97
15.
KramerGBoehringerDBanNBukauB.The ribosome as a platform for co-translational processing, folding and targeting of newly synthesized proteins. Nat Struct Mol Biol2009;
16:589–97
16.
PreisslerSDeuerlingE.Ribosome-associated chaperones as key players in proteostasis. Trends Biochem Sci2012;
37:274–83
17.
PfundCHuangPLopez-HoyoNCraigEA.Divergent functional properties of the ribosome-associated molecular chaperone ssb compared with other Hsp70s. Mol Biol Cell2001;
12:3773–82
18.
HorstMOppligerWRospertSSchöNH-J.Sequential action of two hsp70 complexes during protein import into mitochondria. EMBO J1997;
16:1842–9
19.
VoisineCCraigEAZufallNVon AhsenOPfannerN.VoosWThe protein import motor of mitochondria: unfolding and trapping of preproteins are distinct and separable functions of matrix Hsp70. Cell1999;
97:565–74
20.
BuchbergerABukauBSommerT.Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms. Mol Cell2010;
40:238–52
21.
SchmidSLBraellWASchlossmanDMRothmanJE.A role for clathrin light chains in the recognition of clathrin cages by 'uncoating ATPase'. Nature1984;
311:228–31
22.
SousaRLaferEM.The role of molecular chaperones in clathrin mediated vesicular trafficking. Front Mol Biosci2015;
2:26
23.
SousaRLiaoHSCuéllarJ, JSValpuestaJMJinAJLaferEM.Clathrin-coat disassembly illuminates the mechanisms of Hsp70 force generation. Nat Struct Mol Biol2016;
23:821–9
24.
ArispeNDeM.A. ATP and ADP modulate a cation channel formed by Hsc70 in acidic phospholipid membranes. J Biol Chem2000;
275:30839–43
25.
VegaVLRodríguez-SilvaMFreyTGehrmannMDiazJCSteinemCMulthoffGArispeNDe MaioA.Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol2008;
180:4299–307
26.
AseaAKraeftSKKurt-JonesEAStevensonMAChenLBFinbergRWKooGCCalderwoodSK.HSP70 stimulates cytokine production through a CD 14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med2000;
6:435–42
27.
MilaniVNoessnerEGhoseSKuppnerMAhrensBScharnerAGastparRIsselsRD.Heat shock protein 70: role in antigen presentation and immune stimulation. Int J Hyperthermia2002;
18:563–75
28.
LiberekKMarszalekJAngDGeorgopoulosCZyliczM.Escherichia coli DnaJ and GrpE heat shock proteins jointly stimulate ATPase activity of DnaK. Proc Natl Acad Sci U S A1991;
88:2874–8
29.
ZuiderwegERPBertelsenEBRousakiAMayerMPGestwickiJEAhmadA.Allostery in the Hsp70 chaperone proteins. Top Curr Chem2012;
328:99–153
30.
QiRSarbengEBLiuQLeKQXuXXuHYangJWongJLVorvisCHendricksonWA.Allosteric opening of the polypeptide-binding site when an Hsp70 binds ATP. Nat Struct Mol Biol2013;
20:900–7
31.
BertelsenaEBChangLGestwickiJEZuiderwegERP.Solution conformation of wild-type E. coli Hsp70 (DnaK) chaperone complexed with ADP and substrate. Proc Natl Acad Sci U S A2009;
106:8471–6
32.
KimYEHippMSBracherAHayer-HartlMUlrich HartlF.Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem2013;
82:323–55
33.
RistWGrafCBukauBMayerMP.Amide hydrogen exchange reveals conformational changes in Hsp70 chaperones important for allosteric regulation. J Biol Chem2006;
281:16493–501
34.
BhattacharyaAKurochkinAVYipGNBZhangYBertelsenEBZuiderwegERP.Allostery in Hsp70 chaperones is transduced by subdomain rotations. J Mol Biol2009;
388:475–90
35.
StevensFJArgonY.Protein folding in the ER. Semin Cell Dev Biol1999;
10:443–54
36.
ParodiAJ.Protein glucosylation and its role in protein folding. Annu Rev Biochem2000;
69:69–93
37.
FlahertyKMDeLuca-FlahertyCMcKayDB.Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein. Nature1990;
346:623–8
Jeung-HoiHMcKayDB.ATPase kinetics of recombinant bovine 70 kDa heat shock cognate protein and its amino-terminal ATPase domain. Biochemistry1994;
33:14625–35
40.
AldersonTRKimJHMarkleyJL.Dynamical structures of Hsp70 and Hsp70–Hsp40 complexes.Structure2016;
24:1014–30
41.
BukauBHorwichAL.The Hsp70 and Hsp60 chaperone machines. Cell1998;
92:351–66
42.
BorkPSanderCValenciaA.An ATPase domain common to prokaryotic cell cycle proteins, sugar kinases, actin, and hsp70 heat shock proteins. Proc Natl Acad Sci U S A1992;
89:7290–4
43.
SousaMCMcKayDB.The hydroxyl of threonine 13 of the bovine 70-kDa heat shock cognate protein is essential for transducing the ATP-induced conformational change. Biochemistry1998;
37:15392–9
44.
O'BrienMCFlahertyKMMcKayDB.Lysine 71 of the chaperone protein Hsc70 is essential for ATP hydrolysis. J Biol Chem1996;
271:15874–78
45.
ZhuXZhaoXBurkholderWFGragerovAOgataCMGottesmanMEHendricksonWA.Structural analysis of substrate binding by the molecular chaperone DnaK. Science1996;
272:1606–14
46.
ZahnMBertholdNKieslichBKnappeDHoffmannRSträterN.Structural studies on the forward and reverse binding modes of peptides to the chaperone DnaK. J Mol Biol2013;
425:2463–79
47.
MayerMPSchröderHRüdigerSPaalKLaufenTBukauB.Multistep mechanism of substrate binding determines chaperone activity of Hsp70. Nat Struct Biol2000;
7:586–93
48.
BertelsenEBZhouHLowryDFFlynnGCDahlquistFW.Topology and dynamics of the 10 kDa C-terminal domain of DnaK in solution. Protein Sci2008;
8:343–54
49.
SmockRGBlackburnME.GieraschLM.Conserved, disordered C terminus of DnaK enhances cellular survival upon stress and DnaK in vitro chaperone activity. J Biol Chem2001;
286:31821–9
50.
ScheuflerCBrinkerABourenkovGPegoraroSUlrich HartlFMoarefiIsmailM.Structure of TPR domain–peptide complexes: critical elements in the assembly of the Hsp70–Hsp90 multichaperone machine clemens. Cell2000;
101:199–210
51.
ZhuravlevaAGieraschLM.Substrate-binding domain conformational dynamics mediate Hsp70 allostery. Proc Natl Acad Sci U S A112:E2865–73
52.
KitykRKoppJSinningIMayerMP.Structure and dynamics of the ATP-Bound open conformation of Hsp70 chaperones. Mol Cell2012;
48:863–74
53.
StevensSYCaiSPellecchiaMZuiderwegERP.The solution structure of the bacterial HSP70 chaperone protein domain DnaK(393-507) in complex with the peptide NRLLLTG. Protein Sci2009;
12:2588–96
54.
McCartyJSBuchbergerAReinsteinJBukauB.The role of ATP in the functional cycle of the DnaK chaperone system. J Mol Biol1995;
249:126–37
55.
KarzaiAWMcMackenRA.Bipartite signaling mechanism involved in DnaJ-mediated activation of the Escherichia Coli DnaK protein. J Biol Chem1996;
271:11236–46
56.
SlepenkovSV.WittSN.The unfolding story of the Escherichia Coli Hsp70 DnaK: is DnaK a holdase or an unfoldase?Mol Microbiol2002;
45:1197–206
57.
KitykRVogelMSchlechtRBukauBMayerMP.Pathways of allosteric regulation in Hsp70 chaperones. Nat Commun2015;
6:1–11
58.
Dores-SilvaPRBarbosaLRSRamosCHIBorgesJC.Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity, interaction with adenosine nucleotides, solution structure and domain organization. PLoS One2015;
10:e0117170
59.
da SilvaKPBorgesJC.The molecular chaperone Hsp70 family members function by a bidirectional heterotrophic allosteric mechanism. Protein Pept Lett2011;
18:132–42
60.
ZhuravlevaAClericoEMGieraschLM.An interdomain energetic tug-of-War creates the allosterically active state in Hsp70 molecular chaperones. Cell2012;
151:1296–307
61.
SwainJFDinlerGSivendranRMontgomeryDLStotzMGieraschLM.Hsp70 chaperone ligands control domain association via an allosteric mechanism mediated by the interdomain linker. Mol Cell2007;
26:27–39
62.
PackschiesLTheyssenHBuchbergerABukauBGoodyRSReinsteinJ.GrpE accelerates nucleotide exchange of the molecular chaperone DnaK with an associative displacement mechanism. Biochemistry1997;
36:3417–22
63.
EllisRJHemmingsenSM.Molecular chaperones: proteins essential for the biogenesis of some macromolecular structures. Trends Biochem Sci1989;
14:339–42
64.
BalchinDHayer-HartlMHartlFU.In vivo aspects of protein folding and quality control. Science2016;
353:aac4354
65.
DobsonCMKarplusM.The fundamentals of protein folding: bringing together theory and experiment. Curr Opin Struct Biol1999;
9:92–101
66.
FanC-YLeeSCyrDM.Mechanisms for regulation of Hsp70 function by Hsp40. Cell Stress Chaper2003;
8:309
67.
KampingaHHCraigEA.The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol2010;
11:579–92
68.
NillegodaNBStankAMalinverniDAlbertsNSzlachcicABarducciADe Los RiosPWadeRCBukauB.Evolution of an intricate J-protein network driving protein disaggregation in eukaryotes. Elife2017;
6:3417–22
69.
PierpaoliEVSandmeierESchönfeldHJChristenP.Control of the DnaK chaperone cycle by substoichiometric concentrations of the co-chaperones DnaJ and GrpE. J Biol Chem1998;
273:6643–9
70.
HanWChristenP.Mechanism of the targeting action of DnaJ in the DnaK molecular chaperone system. J Biol Chem2003;
278:19038–43
71.
KitykRKoppJMayerMP.Molecular mechanism of J-domain-triggered ATP hydrolysis by Hsp70 chaperones. Mol Cell2018;
69:227–37
72.
AldersonTRKimJHCaiKFrederickROTonelliMMarkleyJL.The specialized Hsp70 (HscA) interdomain linker binds to its nucleotide-binding domain and stimulates ATP hydrolysis in both cis and trans configurations. Biochemistry2014;
53:7148–59
73.
HallD.On the nature of the optimal form of the Holdase-Type chaperone stress response. FEBS Lett2020;
594:43–66
74.
GenestOWicknerSDoyleSM.Hsp90 and Hsp70 chaperones: collaborators in protein remodeling. J Biol Chem2019;
294:2109–20
75.
AlviraSCuéllarJRöhlAYamamotoSItohHAlfonsoCRivasGBuchnerJValpuestaJM.Structural characterization of the substrate transfer mechanism in Hsp70/Hsp90 folding machinery mediated by hop. Nat Commun2014;
5:5484
76.
MayerMP.Hsp70 chaperone dynamics and molecular mechanism. Trends Biochem Sci2013;
38:507–14
77.
VelascoLDublangLMoroFMugaA.The complex phosphorylation patterns that regulate the activity of Hsp70 and its cochaperones. Int J Mol Sci2019;
20:4122
78.
KundratLReganL.Balance between folding and degradation for Hsp90-dependent client proteins: a key role for CHIP. Biochemistry2010;
49:7428–38
79.
StankiewiczMNikolayRRybinVMayerMP.CHIP participates in protein triage decisions by preferentially ubiquitinating Hsp70-bound substrates. FEBS J2010;
277:3353–67
80.
BallingerCAConnellPWuYHuZThompsonLJYinL-YPattersonC.Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol1999;
19:4535–45
81.
Quintana-GallardoLMartín-BenitoJMarcillaMEspadasGSabidóEValpuestaJM.The cochaperone CHIP marks Hsp70- and Hsp90-bound substrates for degradation through a very flexible mechanism. Sci. Rep2019;
9:1–16
82.
CarrelloAIngleyEMinchinRFTsaiSRatajczakT.The common tetratricopeptide repeat acceptor site for steroid receptor-associated immunophilins and hop is located in the dimerization domain of Hsp90. J Biol Chem1999;
274:2682–9
83.
AssimonVSouthworthDGestwickiJ.Specific binding of tetratricopeptide repeat (TPR) proteins to heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90) is regulated by affinity and phosphorylation. Biochemistry2015;
54:7120–31
84.
SchmidABLaglederSGräwertMARöhlAHagnFWandingerSKCoxMBDemmerORichterKGrollM.The architecture of functional modules in the Hsp90 co-chaperone Sti1/hop. EMBO J2012;
31:1506–17
85.
BrinkerAScheuflerCVon Der MülbeFFleckensteinBHerrmannCJungGMoarefiIUlrich HartlF.Ligand discrimination by TPR domains. Relevance and selectivity of EEVD-recognition in Hsp70·hop·Hsp90 complexes. J Biol Chem2002;
277:19265–75
86.
SmithMCScaglioneKMAssimonVAPaturySThompsonADDickeyCASouthworthDRPaulsonHLGestwickiJEZuiderwegERP.The E3 ubiquitin ligase CHIP and the molecular chaperone Hsc70 form a dynamic, tethered complex. Biochemistry2013;
52:5354–64
87.
ZhangHAmickJChakravartiRSantarriagaSSchlangerSMcGloneCDareMNixJCScaglioneKMStuehrDJ.A bipartite interaction between Hsp70 and CHIP regulates ubiquitination of chaperoned client proteins. Structure2015;
23:472–82
88.
RanekMJOeingCSanchez-HodgeRKokkonen-SimonKMDillardDAslamMIRainerPPMishraSDunkerly-EyringBHolewinskiRJ.CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury. Nat Commun2020;
11:1–12
89.
SharmaDMasisonDC.Single methyl group determines prion propagation and protein degradation activities of yeast heat shock protein (hsp)-70 chaperones Ssa1p and Ssa2p. Proc Natl Acad Sci U S A2011;
108:13665–70
90.
IosefsonOSharonSGoloubinoffPAzemA.Reactivation of protein aggregates by mortalin and Tid1 – the human mitochondrial Hsp70 chaperone system. Cell Stress Chaperones2012;
17:57–66
91.
SimonsJFFerro-NovickSRoseMDHeleniusA.BiP/Kar2p serves as a molecular chaperone during carboxypeptidase Y folding in yeast. J Cell Biol1995;
130:41–9
92.
WangJLeeJLiemDPingP.HSPA5 gene encoding Hsp70 chaperone BiP in the endoplasmic reticulum. Gene2017;
618:14–23
93.
ShorterJ.The mammalian disaggregase machinery: Hsp110 synergizes with Hsp70 and Hsp40 to catalyze protein disaggregation and reactivation in a cell-free system. PLoS One2011;
6:e26319
94.
RauchJNGestwickiJE.Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally distinct complexes in vitro. J Biol Chem2014;
289:1402–14
95.
DongMBridgesJPApsleyKXuYWeaverTE.ERdj4 and ERdj5 are required for endoplasmic reticulum-associated protein degradation of misfolded surfactant protein C. MBoC2008;
19:2620–30
96.
ShomuraYDragovicZChangHCTzvetkovNYoungJCBrodskyJLGuerrieroVHartlFUBracherA.Regulation of Hsp70 function by HspBP1: structural analysis reveals an alternate mechanism for Hsp70 nucleotide exchange. Mol Cell2005;
17:367–79
97.
RosamMKraderDNickelsCHochmairJBackKCAgamGBarthAZeymerCHendrixJSchneiderM.Bap (Sil1) regulates the molecular chaperone BiP by coupling release of nucleotide and substrate. Nat Struct Mol Biol2018;
25:90–100
98.
GowdaNKCKaimalJMKitykRDanielCLiebauJÖhmanMMayerMPAndréassonC.Nucleotide exchange factors Fes1 and HspBP1 mimic substrate to release misfolded proteins from Hsp70. Nat Struct Mol Biol2018;
25:3–89
99.
GowdaNKCKaimalJMMasserAEKangWFriedländerMRAndréassonC.Cytosolic splice isoform of Hsp70 nucleotide exchange factor Fes1 is required for the degradation of misfolded proteins in yeast. Mol Biol Cell2016;
27:1210–9
100.
KabaniMBeckerichJ-MGaillardinC.Sls1p stimulates Sec63p-mediated activation of Kar2p in a conformation-dependent manner in the yeast endoplasmic reticulum. Mol Cell Biol2000;
20:6923–34
101.
ChungKTShenYHendershotLM.BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP. J Biol Chem2002;
277:47557–63
102.
BhattacharyaKWeidenauerLLuengoTMPietersECEcheverríaPCBernasconiLWiderDSadianYKoopmanMBVilleminM.The Hsp70-Hsp90 co-chaperone hop/Stip1 shifts the proteostatic balance from folding towards degradation. Nat Commun2020;
11:5975
103.
KumarNGaurDMasisonDCSharmaD.The BAG homology domain of Snl1 cures yeast prion [URE3] through regulation of Hsp70 chaperones.G32014;
4:461–70
104.
TakayamaSReedJC.Molecular chaperone targeting and regulation by BAG family proteins. Nat Cell Biol2001;
3:E237–41
105.
KabbageMDickmanMB.The BAG proteins: a ubiquitous family of chaperone regulators. Cell Mol Life Sci2008;
65:1390–402
106.
ZuoDSubjeckJWangXY.Unfolding the role of large heat shock proteins: new insights and therapeutic implications. Front Immunol2016;
7:1
107.
EastonDPKanekoYSubjeckJR.The Hsp110 and Grp170 stress proteins: newly recognized relatives of the Hsp70s. Cell Stress Chaper2000;
5:276–90
108.
LiuQHendricksonWA.Insights into Hsp70 chaperone activity from a crystal structure of the yeast Hsp110 Sse1. Cell2007;
131:106–20
109.
RaviolHSadlishHRodriguezFMayerMPBukauB.Chaperone network in the yeast cytosol: Hsp110 is revealed as an Hsp70 nucleotide exchange factor. EMBO J2006;
25:2510–8
LiZHartlFUBracherA.Structure and function of hip, an attenuator of the Hsp70 chaperone cycle. Nat Struct Mol Biol2013;
20:929–35
112.
GebauerMZeinerM.GehringUProteins interacting with the molecular chaperone Hsp70/Hsc70: physical associations and effects on refolding activity. FEBS Lett1997;
417:109–13
113.
FerreiraJVSoaresARRamalhoJSRibeiro-RodriguesTMáximoCZuzarteMGirãoHPereiraP.Exosomes and STUB1/CHIP cooperate to maintain intracellular proteostasis. PLoS One2019;
14:e0223790
114.
HarrisonC.GrpE, a nucleotide exchange factor for DnaK. Cell Stress Chaper2003;
8:218–24
115.
ZapunAJakobCAThomasDYBergeronJJM.Protein folding in a specialized compartment: the endoplasmic reticulum. Structure1999;
7:R173–82
116.
SondermannHScheuflerCSchneiderCHöhfeldJHartlFUMoarefiI.Structure of a bag/Hsc70 complex: convergent functional evolution of Hsp70 nucleotide exchange factors. Science2001;
291:1553–7
117.
ZhangMWindheimMRoeSMPeggieMCohenPProdromouCPearlLH.Chaperoned ubiquitylation – crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex. Mol Cell2005;
20:525–38
118.
NakamuraATakumiKMikiK.Crystal structure of a thermophilic GrpE protein: insight into thermosensing function for the DnaK chaperone system. J Mol Biol2010;
396:1000–11
119.
HarrisonCJHayer-HartlMDi LibertoMHartlFUKuriyanJ.Crystal structure of the nucleotide exchange factor GrpE bound to the ATPase domain of the molecular chaperone DnaK. Science1997;
276:431–5
120.
PellecchiaMSzyperskiTWallDGeorgopoulosCWüthrichK.NMR structure of the J-domain and the gly/Phe-rich region of the Escherichia coli DnaJ chaperone. J Mol Biol1996;
260:236–50
121.
PolierSDragovicZHartlFUBracherA.Structural basis for the cooperation of Hsp70 and Hsp110 chaperones in protein folding. Cell2008;
133:1068–79
122.
CheethamMECaplanAJ.Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function. Cell Stress Chaper1998;
3:28–36
123.
OhtsukaKHataM.Molecular chaperone function of mammalian Hsp70 and Hsp40 – a review. Int J Hyperthermia2000;
16:231–45
124.
XuZPageRCGomesMMKohliENixJCHerrABPattersonCMisraS.Structural basis of nucleotide exchange and client binding by the Hsp70 cochaperone Bag2. Nat Struct Mol Biol2008;
15:1309–17
125.
MeleroRMoroFPérez-CalvoMÁPerales-CalvoJQuintana-GallardoLLlorcaOMugaAValpuestaJM.Modulation of the chaperone DnaK allosterism by the nucleotide exchange factor GrpE. J Biol Chem2015;
290:10083–92
126.
RauchJNZuiderwegERPGestwickiJE.Non-Canonical interactions between heat shock cognate protein 70 (Hsc70) and Bcl2-associated anthanogene (BAG) Co-Chaperones are important for client release. J Biol Chem2016;
29:19848–57
127.
LüdersJDemandJHöhfeldJ.The Ubiquitin-Related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome. J Biol Chem2000;
275:4613–7
128.
LinEHBVon KorffMPetersonDLudmanEJCiechanowskiPKatonW.Structural basis of nucleotide exchange and client binding by the novel Hsp70-Cochaperone Bag2. Am J Manag Care2014;
20:887–93
129.
StürnerEBehlC.The role of the multifunctional Bag3 protein in cellular protein quality control and in disease. Front Mol Neurosci2017;
10:177
130.
KuwabaraNMinamiRYokotaNMatsumotoHSendaTKawaharaHKatoR.Structure of a BAG6 (bcl-2-associated athanogene 6)-Ubl4a (ubiquitin-like protein 4a) complex reveals a novel binding interface that functions in tail-anchored protein biogenesis. J Biol Chem2015;
290:9387–98
131.
TakayamaSBimstonDNMatsuzawaSIFreemanBCAime-SempeCXieZMorimotoRIReedJC.BAG-1 modulates the chaperone activity of Hsp70/Hsc70. EMBO J1997;
16:4887–96
132.
HantoucheCWilliamsonBValinskyWCSolomonJShrierAYoungJC.Bag1 co-chaperone promotes TRC8 E3 ligase-dependent degradation of misfolded human ether a go-go-related gene (HERG) potassium channels. J Biol Chem2017;
292:2287–300
133.
CabreraYDublangLAngel Fernández-HigueroJAlbesa-JovéDLucasMVigueraARGuerinMEVilarJMGMugaAMoroF.Regulation of human Hsc70 ATPase and chaperone activities by Apg2: role of the acidic subdomain. J Mol Biol2018;
431:444–61
134.
AndréassonCFiauxJRampeltHDruffel-AugustinSBukauB.Insights into the structural dynamics of the Hsp110-Hsp70 interaction reveal the mechanism for nucleotide exchange activity. Proc Natl Acad Sci U S A2008;
105:16519–24
135.
DragovicZBroadleySAShomuraYBracherAHartlFU.Molecular chaperones of the Hsp110 family act as nucleotide exchange factors of Hsp70s. EMBO J2006;
25:2519–28
136.
IrmerHHöhfeldJ.Characterization of functional domains of the eukaryotic co-chaperone hip. J Biol Chem1997;
272:2230–5
137.
HöfeldJMinamiYHartlFU.Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hsp40 reaction cycle. Cell1995;
83:589–98
138.
ShiZ-ZZhangJ-WZhengS.What we know about ST13, a Co-Factor of heat shock protein, or a tumor suppressor?J Zhejiang Univ Sci B2007;
8:170–6
139.
HöhfeldJJentschS.GrpE-like regulation of the Hsc70 chaperone by the anti-apoptotic protein BAG-1. EMBO J1997;
16:6209–16
140.
BuczynskiGSlepenkovSVSehornMGWittSN.Characterization of a lidless form of the molecular chaperone DnaK: deletion of the lid increases peptide on- and off-Rate constants. J Biol Chem2001;
276:27231–6
141.
ClericoEMTilitskyJMMengWGieraschLM.How Hsp70 molecular machines interact with their substrates to mediate diverse physiological functions. J Mol Biol2015;
427:1575–88
142.
RüdigerSBuchbergerABukauB.Interaction of Hsp70 chaperones with substrates. Nat Struct Biol1997;
4:342–9
143.
NunesJMMayer-HartlMHartlFUMüllerDJ.Action of the Hsp70 chaperone system observed with single proteins. Nat Commun2015;
6:6307
144.
RodriguezFArsène-PloetzeFRistWRüdigerSSchneider-MergenerJMayerMPBukauB.Molecular basis for regulation of the heat shock transcription factor Σ32 by the DnaK and DnaJ chaperones. Mol Cell2008;
32:347–58
145.
SerlidakiDvan WaardeMAWHRohlandLWentinkASDekkerSLKamphuisMJBoertienJMBrunstingJFNillegodaNBBukauB.Functional diversity between HSP70 paralogs caused by variable interactions with specific co-chaperones. J Biol Chem2020;
295:7301–16
146.
SekharASantiagoMLamHNLeeJHCavagneroS.Transient interactions of a slow-folding protein with the Hsp70 chaperone machinery. Protein Sci2012;
21:1042–55
KellnerRHofmannHBarducciAWunderlichBNettelsDSchulerB.Single-Molecule spectroscopy reveals chaperone-mediated expansion of substrate protein. Proc Natl Acad Sci U S A2014;
111:13355–60
149.
ChenZKurtNRajagopalanSCavagneroS.Secondary structure mapping of DnaK-Bound protein fragments: chain helicity and local helix unwinding at the binding Site. Biochemistry2006;
45:12325–33
150.
SekharALamHNCavagneroS.Protein folding rates and thermodynamic stability are key determinants for interaction with the Hsp70 chaperone system. Protein Sci2012;
21:1489–1502
151.
RosenzweigRSekharANageshJKayLE.Promiscuous binding by Hsp70 results in conformational heterogeneity and fuzzy chaperone-substrate ensembles. Elife2017;
6:1–22
152.
FourieAMSambrookJFGethingMJH.Common and divergent peptide binding specificities of Hsp70 molecular chaperones. J Biol Chem1994;
269:30470–8
153.
RüdigerSGermerothLSchneider-MergenerJBukauB.Substrate specificity of the DnaK chaperone determined by screening cellulose-bound peptide libraries. EMBO J1997;
16:1501–7
154.
SwainJFSchulzEGGieraschLM.Direct comparison of a stable isolated Hsp70 substrate-binding domain in the empty and substrate-bound states. J Biol Chem2006;
281:1605–11
155.
JiangJPrasadKLaferEMSousaR.Structural basis of interdomain communication in the Hsc70 chaperone. Mol Cell2005;
20:513–24
156.
AttisanoLTuen Lee-HoeflichS.
The smads. Genome Biol2001;
2:reviews3010.1
157.
LiRFShangYLiuDRenZSChangZSuiSF.Differential ubiquitination of Smad1 mediated by CHIP: implications in the regulation of the bone morphogenetic protein signaling pathway. J Mol Biol2007;
374:777–90
158.
ImamuraTOshimaYHikitaA.Regulation of TGF-β family signalling by ubiquitination and deubiquitination. J Biochem2013;
154:481–9
159.
WangLLiuYTHaoRChenLChangZWangHRWangZXWuJW.Molecular mechanism of the negative regulation of Smad1/5 protein by carboxyl terminus of Hsc70-Interacting protein (CHIP). J Biol Chem2011;
286:15883–94
160.
LiuJBaoJHaoJPengYHongF.HSP70 inhibits high Glucose-Induced Smad3 activation and attenuates epithelial-to-Mesenchymal transition of peritoneal mesothelial cells. Mol Med Rep2014;
10:1089–95
161.
SeoJHanSYSeongDHanHJSongJ.Multifaceted C-Terminus of HSP70-Interacting protein regulates tumorigenesis via protein quality control. Arch Pharm Res2019;
42:63–75
162.
ShangYXuXDuanXGuoJWangYRenFHeDChangZ.Hsp70 and Hsp90 oppositely regulate TGF-β signaling through CHIP/Stub1. Biochem Biophys Res Commun2014;
446:387–92
163.
XinHXuXLiLNingHRongYShangYWangYFuXYChangZ.CHIP controls the sensitivity of transforming growth factor-β signaling by modulating the basal level of Smad3 through Ubiquitin-Mediated degradation. J Biol Chem2005;
280:20842–50
164.
AntognelliCGambelungheAMuziGTalesaVN.Glyoxalase i drives epithelial-to-Mesenchymal transition via Argpyrimidine-Modified Hsp70, MiR-21 and SMAD signalling in human bronchial cells BEAS-2B chronically exposed to crystalline silica Min-U-Sil 5: transformation into a neoplastic-like phenotype. Free Radic Biol Med2016;
92:110–25
165.
HassanAQKirbyCAZhouWSchuhmannTKitykRKippDRBairdJChenJChenYChungF.The novolactone natural product disrupts the allosteric regulation of Hsp70. Chem Biol2015;
22:87–97
166.
EdkinsALPriceJTGraham PockleyABlatchGL.Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective. Philos Trans R Soc B Biol Sci2018;
373:DOI: 10.1098/rstb.2016.0521
167.
GeraciFTurturiciGSconzoG.Hsp70 and its molecular role in nervous system diseases. Biochem Res Int2011;
2011:DOI: 10.1155/2011/618127
168.
PaturySMiyataYGestwickiJ.Pharmacological targeting of the Hsp70 chaperone. Curr Top Med Chem2009;
9:1337–51
169.
KaliaSKLeeSSmithPDLiuLCrockerSJThorarinsdottirTEGloverJRFonEAParkDSLozanoAM.BAG5 inhibits parkin and enhances dopaminergic neuron degeneration. Neuron2004;
44:931–45
170.
BehlC.Breaking BAG: the co-Chaperone BAG3 in health and disease. Trends Pharmacol Sci2016;
37:672–88
171.
HasegawaTYoshidaSSugenoNKobayashiJAokiM.DnaJ/Hsp40 family and Parkinson’s disease. Front Neurosci2018;
11:743
172.
HowarthJLKellySKeaseyMPGloverCPJLeeYBMitrophanousKChappleJPGalloJMCheethamMEUneyJB.Hsp40 molecules that target to the Ubiquitin-Proteasome system decrease inclusion formation in models of polyglutamine disease. Mol Ther2007;
15:1100–5
173.
LackieREMaciejewskiAOstapchenkoVGMarques-LopesJChoyWYDuennwaldMLPradoVFPradoMAM.The Hsp70/Hsp90 chaperone machinery in neurodegenerative diseases. Front Neurosci2017;
11:254
174.
ZhaoTHongYYinPLiSLiXJ.Differential HspBP1 expression accounts for the greater vulnerability of neurons than astrocytes to misfolded proteins. Proc Natl Acad Sci U S A2017;
114:E7803–11
175.
TaguchiYVGorenbergELNagyMThrasherDFentonWAVolpicelli-DaleyLHorwichALChandraSS.Hsp110 mitigates α-Synuclein pathology in vivo. Proc Natl Acad Sci U S A2019;
116:24310–6
176.
Dorard C, De Thonel A, Collura A, Marisa L, Svrcek M, Lagrange A, Jego G, Wanherdrick K, Joly AL, Buhard O, Gobbo J, Penard-Lacronique V, Zouali H, Tubacher E, Kirzin S, Selves J, Milano G, Etienne-Grimaldi MC, Bengrine-Lefevre L, Louvet C, Tournigand C, Lefvre JH, Parc Y, Tiret E, Fléjou JF, Gaub MP, Garrido C, Duval A.
Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis. Nat Med2011;
17:1283–9
177.
ZhangSHuZWMaoCYShiCHXuYM.CHIP as a therapeutic target for neurological diseases. Cell Death Dis2020;
11:1–12
178.
HayerSNDeconinckTBenderBSmetsKZüchnerSReichSSchölsLSchüleRDe JonghePBaetsJSynofzikM.STUB1/CHIP mutations cause gordon holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations. Orphanet J Rare Dis2017;
12:31
179.
Synofzik M, Schüle R, Schulze M, Gburek-Augustat J, Schweizer R, Schirmacher A, Krögeloh-Mann I, Gonzalez M, Young P, Züchner S, Schöls L, Bauer P.
Phenotype and frequency of STUB1 mutations: next-generation screenings in caucasian ataxia and spastic paraplegia cohorts. Orphanet J Rare Dis2014;
9:57
