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PMID: 20453930 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Mechanisms of the Hsp70 chaperone system.

Biochemistry and cell biology = Biochimie et biologie cellulaire ·Vol. 88 ·No. 2 ·2010-04-00 ·Pages 291-300

Young JC

Abstract

Molecular chaperones of the Hsp70 family have diverse functions in cells. They assist the folding of newly synthesized and stress-denatured proteins, as well as the import of proteins into organelles, and the dissociation of aggregated proteins. The well-conserved Hsp70 chaperones are ATP dependent: binding and hydrolysis of ATP regulates their interactions with unfolded polypeptide substrates, and ATPase cycling is necessary for their function. All cellular functions of Hsp70 chaperones use the same mechanism of ATP-driven polypeptide binding and release. The Hsp40 co-chaperones stimulate ATP hydrolysis by Hsp70 and the type 1 Hsp40 proteins are conserved from Escherichia coli to humans. Various nucleotide exchange factors also promote the Hsp70 ATPase cycle. Recent advances have added to our understanding of the Hsp70 mechanism at a molecular level.

MeSH Terms
Adenosine Triphosphate/metabolism HSP70 Heat-Shock Proteins/chemistry,metabolism Sodium-Potassium-Exchanging ATPase/chemistry,metabolism
Chemicals
HSP70 Heat-Shock Proteins Adenosine Triphosphate Sodium-Potassium-Exchanging ATPase
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Young Jason C
Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada.
References (81)
81 references, click to expand
  1. Nuclear magnetic resonance solution structure of the human Hsp40 (HDJ-1) J-domain.
    J Mol Biol. 1996 Jul 12;260(2):224-35 PMID: 8764402
  2. Defining the requirements for Hsp40 and Hsp70 in the Hsp90 chaperone pathway.
    J Biol Chem. 2006 Sep 8;281(36):26235-44 PMID: 16854979
  3. Low resolution structural study of two human HSP40 chaperones in solution. DJA1 from subfamily A and DJB4 from subfamily B have different quaternary structures.
    J Biol Chem. 2005 Apr 8;280(14):13671-81 PMID: 15661747
  4. The type I Hsp40 zinc finger-like region is required for Hsp70 to capture non-native polypeptides from Ydj1.
    J Biol Chem. 2005 Jan 7;280(1):695-702 PMID: 15496404
  5. The crystal structure of the yeast Hsp40 Ydj1 complexed with its peptide substrate.
    Structure. 2003 Dec;11(12):1475-83 PMID: 14656432
  6. Mutations in the substrate binding domain of the Escherichia coli 70 kDa molecular chaperone, DnaK, which alter substrate affinity or interdomain coupling.
    J Mol Biol. 1999 Feb 26;286(3):915-32 PMID: 10024459
  7. The human DnaJ homologue dj2 facilitates mitochondrial protein import and luciferase refolding.
    J Cell Biol. 1997 Dec 1;139(5):1089-95 PMID: 9382858
  8. The Hsp70 and Hsp60 chaperone machines.
    Cell. 1998 Feb 6;92(3):351-66 PMID: 9476895
  9. Hsp110 is a nucleotide-activated exchange factor for Hsp70.
    J Biol Chem. 2008 Apr 4;283(14):8877-84 PMID: 18218635
  10. Structural basis for the cooperation of Hsp70 and Hsp110 chaperones in protein folding.
    Cell. 2008 Jun 13;133(6):1068-79 PMID: 18555782
  11. Multistep mechanism of substrate binding determines chaperone activity of Hsp70.
    Nat Struct Biol. 2000 Jul;7(7):586-93 PMID: 10876246
  12. Structural basis of interdomain communication in the Hsc70 chaperone.
    Mol Cell. 2005 Nov 23;20(4):513-24 PMID: 16307916
  13. Ionic contacts at DnaK substrate binding domain involved in the allosteric regulation of lid dynamics.
    J Biol Chem. 2006 Mar 17;281(11):7479-88 PMID: 16415343
  14. Structural analysis of substrate binding by the molecular chaperone DnaK.
    Science. 1996 Jun 14;272(5268):1606-14 PMID: 8658133
  15. Characterization of Hsp70 binding and nucleotide exchange by the yeast Hsp110 chaperone Sse1.
    Biochemistry. 2006 Dec 19;45(50):15075-84 PMID: 17154545
  16. Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function.
    Cell Stress Chaperones. 1998 Mar;3(1):28-36 PMID: 9585179
  17. Molecular chaperones of the Hsp110 family act as nucleotide exchange factors of Hsp70s.
    EMBO J. 2006 Jun 7;25(11):2519-28 PMID: 16688212
  18. The roles of the two zinc binding sites in DnaJ.
    J Biol Chem. 2003 Nov 7;278(45):44457-66 PMID: 12941935
  19. Structural basis of nucleotide exchange and client binding by the Hsp70 cochaperone Bag2.
    Nat Struct Mol Biol. 2008 Dec;15(12):1309-17 PMID: 19029896
  20. Exchangeable chaperone modules contribute to specification of type I and type II Hsp40 cellular function.
    Mol Biol Cell. 2004 Feb;15(2):761-73 PMID: 14657253
  21. Solution conformation of wild-type E. coli Hsp70 (DnaK) chaperone complexed with ADP and substrate.
    Proc Natl Acad Sci U S A. 2009 May 26;106(21):8471-6 PMID: 19439666
  22. The crystal structure of the C-terminal fragment of yeast Hsp40 Ydj1 reveals novel dimerization motif for Hsp40.
    J Mol Biol. 2005 Mar 4;346(4):1005-11 PMID: 15701512
  23. Human DnaJ homologs dj2 and dj3, and bag-1 are positive cochaperones of hsc70.
    J Biol Chem. 2000 Aug 11;275(32):24728-34 PMID: 10816573
  24. The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones.
    Cell Mol Life Sci. 2006 Nov;63(22):2560-70 PMID: 16952052
  25. Structure-function analysis of the zinc finger region of the DnaJ molecular chaperone.
    J Biol Chem. 1996 Jun 21;271(25):14840-8 PMID: 8662861
  26. The allosteric transition in DnaK probed by infrared difference spectroscopy. Concerted ATP-induced rearrangement of the substrate binding domain.
    Protein Sci. 2006 Feb;15(2):223-33 PMID: 16384998
  27. Bag-1M accelerates nucleotide release for human Hsc70 and Hsp70 and can act concentration-dependent as positive and negative cofactor.
    J Biol Chem. 2001 Aug 31;276(35):32538-44 PMID: 11441021
  28. Structure-based mutagenesis studies of the peptide substrate binding fragment of type I heat-shock protein 40.
    Biochem J. 2005 Mar 15;386(Pt 3):453-60 PMID: 15500443
  29. Molecular chaperones in the cytosol: from nascent chain to folded protein.
    Science. 2002 Mar 8;295(5561):1852-8 PMID: 11884745
  30. Allosteric regulation of Hsp70 chaperones involves a conserved interdomain linker.
    J Biol Chem. 2006 Dec 15;281(50):38705-11 PMID: 17052976
  31. Allosteric regulation of Hsp70 chaperones by a proline switch.
    Mol Cell. 2006 Feb 3;21(3):359-67 PMID: 16455491
  32. Hsp70 chaperones: cellular functions and molecular mechanism.
    Cell Mol Life Sci. 2005 Mar;62(6):670-84 PMID: 15770419
  33. Structure of the Hsp110:Hsc70 nucleotide exchange machine.
    Mol Cell. 2008 Jul 25;31(2):232-43 PMID: 18550409
  34. Mechanism of the targeting action of DnaJ in the DnaK molecular chaperone system.
    J Biol Chem. 2003 May 23;278(21):19038-43 PMID: 12654915
  35. Overexpression of yeast Hsp110 homolog Sse1p suppresses ydj1-151 thermosensitivity and restores Hsp90-dependent activity.
    Mol Biol Cell. 2002 Aug;13(8):2760-70 PMID: 12181344
  36. Modulation of chaperone activities of Hsp70 and Hsp70-2 by a mammalian DnaJ/Hsp40 homolog, DjA4.
    J Biochem. 2004 Feb;135(2):193-200 PMID: 15047721
  37. Conserved central domains control the quaternary structure of type I and type II Hsp40 molecular chaperones.
    J Mol Biol. 2008 Oct 31;383(1):155-66 PMID: 18723025
  38. HspBP1, a homologue of the yeast Fes1 and Sls1 proteins, is an Hsc70 nucleotide exchange factor.
    FEBS Lett. 2002 Nov 6;531(2):339-42 PMID: 12417338
  39. Regulated association of misfolded endoplasmic reticulum lumenal proteins with P58/DNAJc3.
    EMBO J. 2008 Nov 5;27(21):2862-72 PMID: 18923430
  40. Insights into Hsp70 chaperone activity from a crystal structure of the yeast Hsp110 Sse1.
    Cell. 2007 Oct 5;131(1):106-20 PMID: 17923091
  41. Structure of a Bag/Hsc70 complex: convergent functional evolution of Hsp70 nucleotide exchange factors.
    Science. 2001 Feb 23;291(5508):1553-7 PMID: 11222862
  42. Not all J domains are created equal: implications for the specificity of Hsp40-Hsp70 interactions.
    Protein Sci. 2005 Jul;14(7):1697-709 PMID: 15987899
  43. Amide hydrogen exchange reveals conformational changes in hsp70 chaperones important for allosteric regulation.
    J Biol Chem. 2006 Jun 16;281(24):16493-501 PMID: 16613854
  44. Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein.
    Nature. 1990 Aug 16;346(6285):623-8 PMID: 2143562
  45. More than folding: localized functions of cytosolic chaperones.
    Trends Biochem Sci. 2003 Oct;28(10):541-7 PMID: 14559183
  46. The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions.
    FEBS Lett. 2007 Jul 31;581(19):3702-10 PMID: 17544402
  47. Mutations in the interdomain linker region of DnaK abolish the chaperone action of the DnaK/DnaJ/GrpE system.
    FEBS Lett. 2001 May 18;497(1):55-8 PMID: 11376662
  48. The ATP hydrolysis-dependent reaction cycle of the Escherichia coli Hsp70 system DnaK, DnaJ, and GrpE.
    Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10345-9 PMID: 7937953
  49. A type I DnaJ homolog, DjA1, regulates androgen receptor signaling and spermatogenesis.
    EMBO J. 2005 Feb 9;24(3):611-22 PMID: 15660130
  50. A role for the Hsp40 Ydj1 in repression of basal steroid receptor activity in yeast.
    Mol Cell Biol. 2000 May;20(9):3027-36 PMID: 10757787
  51. Direct comparison of a stable isolated Hsp70 substrate-binding domain in the empty and substrate-bound states.
    J Biol Chem. 2006 Jan 20;281(3):1605-11 PMID: 16275641
  52. Hsp70 chaperone ligands control domain association via an allosteric mechanism mediated by the interdomain linker.
    Mol Cell. 2007 Apr 13;26(1):27-39 PMID: 17434124
  53. Functional divergence between co-chaperones of Hsc70.
    J Biol Chem. 2008 Oct 3;283(40):27100-9 PMID: 18684711
  54. Identification of a consensus motif in substrates bound by a Type I Hsp40.
    Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11073-8 PMID: 19549854
  55. Domain requirements of DnaJ-like (Hsp40) molecular chaperones in the activation of a steroid hormone receptor.
    J Biol Chem. 1999 Nov 26;274(48):34045-52 PMID: 10567371
  56. Farnesylation of Ydj1 is required for in vivo interaction with Hsp90 client proteins.
    Mol Biol Cell. 2008 Dec;19(12):5249-58 PMID: 18829866
  57. NMR investigations of allosteric processes in a two-domain Thermus thermophilus Hsp70 molecular chaperone.
    J Mol Biol. 2005 May 27;349(1):163-83 PMID: 15876376
  58. Chaperone network in the yeast cytosol: Hsp110 is revealed as an Hsp70 nucleotide exchange factor.
    EMBO J. 2006 Jun 7;25(11):2510-8 PMID: 16688211
  59. Regulation of Hsp70 function by HspBP1: structural analysis reveals an alternate mechanism for Hsp70 nucleotide exchange.
    Mol Cell. 2005 Feb 4;17(3):367-79 PMID: 15694338
  60. Network of general and specialty J protein chaperones of the yeast cytosol.
    Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7163-8 PMID: 17438278
  61. The type I Hsp40 Ydj1 utilizes a farnesyl moiety and zinc finger-like region to suppress prion toxicity.
    J Biol Chem. 2009 Feb 6;284(6):3628-39 PMID: 19056735
  62. Pathways of chaperone-mediated protein folding in the cytosol.
    Nat Rev Mol Cell Biol. 2004 Oct;5(10):781-91 PMID: 15459659
  63. Mechanism of regulation of hsp70 chaperones by DnaJ cochaperones.
    Proc Natl Acad Sci U S A. 1999 May 11;96(10):5452-7 PMID: 10318904
  64. The J-protein family: modulating protein assembly, disassembly and translocation.
    EMBO Rep. 2004 Jun;5(6):567-71 PMID: 15170475
  65. Structural insights into substrate binding by the molecular chaperone DnaK.
    Nat Struct Biol. 2000 Apr;7(4):298-303 PMID: 10742174
  66. Regulated release of ERdj3 from unfolded proteins by BiP.
    EMBO J. 2008 Nov 5;27(21):2873-82 PMID: 18923428
  67. Tuning of chaperone activity of Hsp70 proteins by modulation of nucleotide exchange.
    Nat Struct Biol. 2001 May;8(5):427-32 PMID: 11323718
  68. DnaK, DnaJ and GrpE form a cellular chaperone machinery capable of repairing heat-induced protein damage.
    EMBO J. 1993 Nov;12(11):4137-44 PMID: 7900997
  69. The conserved carboxyl terminus and zinc finger-like domain of the co-chaperone Ydj1 assist Hsp70 in protein folding.
    J Biol Chem. 1998 Mar 6;273(10):5970-8 PMID: 9488737
  70. Multiple 40-kDa heat-shock protein chaperones function in Tom70-dependent mitochondrial import.
    Mol Biol Cell. 2007 Sep;18(9):3414-28 PMID: 17596514
  71. Insights into the structural dynamics of the Hsp110-Hsp70 interaction reveal the mechanism for nucleotide exchange activity.
    Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16519-24 PMID: 18948593
  72. Crystal structures of the 70-kDa heat shock proteins in domain disjoining conformation.
    J Biol Chem. 2008 May 30;283(22):15502-11 PMID: 18400763
  73. Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70.
    Cell. 2003 Jan 10;112(1):41-50 PMID: 12526792
  74. Structural basis of J cochaperone binding and regulation of Hsp70.
    Mol Cell. 2007 Nov 9;28(3):422-33 PMID: 17996706
  75. Escherichia coli DnaJ and GrpE heat shock proteins jointly stimulate ATPase activity of DnaK.
    Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2874-8 PMID: 1826368
  76. Molecular chaperone targeting and regulation by BAG family proteins.
    Nat Cell Biol. 2001 Oct;3(10):E237-41 PMID: 11584289
  77. An essential role for the substrate-binding region of Hsp40s in Saccharomyces cerevisiae.
    J Cell Biol. 2001 Feb 19;152(4):851-6 PMID: 11266475
  78. Hsp110 protects heat-denatured proteins and confers cellular thermoresistance.
    J Biol Chem. 1997 Dec 12;272(50):31636-40 PMID: 9395504
  79. Crystal structure of the nucleotide exchange factor GrpE bound to the ATPase domain of the molecular chaperone DnaK.
    Science. 1997 Apr 18;276(5311):431-5 PMID: 9103205
  80. GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1.
    EMBO J. 1997 Oct 15;16(20):6209-16 PMID: 9321400
  81. The Hdj-2/Hsc70 chaperone pair facilitates early steps in CFTR biogenesis.
    EMBO J. 1999 Mar 15;18(6):1492-505 PMID: 10075921
Article Info
Journal
Biochemistry and cell biology = Biochimie et biologie cellulaire
Abbr.
Biochem Cell Biol
ISSN
1208-6002
DOI
10.1139/o09-175
Published
2010-04-00
Pages
291-300
Language
English
Region
Canada
NLM ID
8606068
PMCID
PMC5026485
Subset
IM
Grants
PHS HHS · 103329-1 · United States
PHS HHS · 70306-1 · United States
CIHR · 68825-2 · Canada
CIHR · 103329-1 · Canada
CIHR · MOP-68825 · Canada
PHS HHS · 68825-2 · United States
CIHR · 70306-1 · Canada
External Links
PubMed source DOI: 10.1139/o09-175 PMC Full Text View journal details
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