Hsp70: A Multi-Tasking Chaperone at the Crossroad of Cellular Proteostasis

  • Vignesh Kumar
  • Koyeli MapaEmail author
Part of the Heat Shock Proteins book series (HESP, volume 13)


Molecular chaperones are key components of protein quality control machineries in all biological systems. Members of Hsp70 group of molecular chaperones are one of the most commonly found chaperones that accomplish multitude of cellular activities in concert with its co-chaperones. Hsp70s are involved in almost all aspects of protein quality control starting from de novo protein folding, prevention of misfolded or aggregated protein formation to membrane translocation and degradation of terminally misfolded proteins. Barring few exceptions, all known Hsp70s accomplish cellular activities by consuming energies from ATP-hydrolysis by their ATPase activity. The ATP-hydrolysis-driven chaperoning activities of Hsp70s are always assisted and regulated by two groups of co-chaperones; J-domain proteins (JDPs) or Hsp40s and nucleotide exchange factors (NEFs), to accomplish cellular functions in physiological time frames. As the co-chaperones especially the JDPs outnumber the Hsp70s, it is thought that different co-chaperone networks actually bestow the multi-tasking ability to particular Hsp70. In this chapter, an overview of recent understanding of various cellular activities of Hsp70s assisted by its co-chaperones have been discussed to highlight the extent of diversity of cellular functions achieved by this group of molecular chaperones.


Heat shock proteins Hsp70 Molecular chaperones Protein folding Proteostasis 



We sincerely acknowledge Dr. Kausik Chakraborty, Asmita Ghsoh and Joshua Jebakumar Peter for their critical comments on the chapter.


  1. Amm, I., Sommer, T., & Wolf, D. H. (2014). Protein quality control and elimination of protein waste: The role of the ubiquitin-proteasome system. Biochimica et Biophysica Acta, 1843, 182–196.PubMedCrossRefGoogle Scholar
  2. Arias, E., & Cuervo, A. M. (2011). Chaperone-mediated autophagy in protein quality control. Current Opinion in Cell Biology, 23, 184–189.PubMedCrossRefGoogle Scholar
  3. Banerjee, R., Jayaraj, G. G., Peter, J. J., Kumar, V., & Mapa, K. (2016). Monitoring conformational heterogeneity of the lid of DnaK substrate-binding domain during its chaperone cycle. The FEBS Journal, 283, 2853–2868.PubMedCrossRefGoogle Scholar
  4. Behnke, J., Feige, M. J., & Hendershot, L. M. (2015). BiP and its nucleotide exchange factors Grp170 and Sil1: Mechanisms of action and biological functions. Journal of Molecular Biology, 427, 1589–1608.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bertelsen, E.B., Chang, L., Gestwicki, J.E., Zuiderweg, E.R. (2009). Solution conformation of wild-type E. coli Hsp70 (DnaK) chaperone complexed with ADP and substrate. Proceedings of the National Academy of Sciences of the United States of America 106, 8471–8476.CrossRefGoogle Scholar
  6. Blamowska, M., Sichting, M., Mapa, K., Mokranjac, D., Neupert, W., & Hell, K. (2010). ATPase domain and interdomain linker play a key role in aggregation of mitochondrial Hsp70 chaperone Ssc1. The Journal of Biological Chemistry, 285, 4423–4431.PubMedCrossRefGoogle Scholar
  7. Blom, J., Kubrich, M., Rassow, J., et al. (1993). The essential yeast protein MIM44 (encoded by MPI1) is involved in an early step of preprotein translocation across the mitochondrial inner membrane. Molecular and Cellular Biology, 13, 7364–7371.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bolender, N., Sickmann, A., Wagner, R., Meisinger, C., & Pfanner, N. (2008). Multiple pathways for sorting mitochondrial precursor proteins. EMBO Reports, 9, 42–49.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bracher, A., & Verghese, J. (2015). GrpE, Hsp110/Grp170, HspBP1/Sil1 and BAG domain proteins: Nucleotide exchange factors for Hsp70 molecular chaperones. Sub-Cellular Biochemistry, 78, 1–33.PubMedCrossRefGoogle Scholar
  10. Casas, C. (2017). GRP78 at the Centre of the Stage in cancer and neuroprotection. Frontiers in Neuroscience, 11, 177.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Chang, Y. W., Sun, Y. J., Wang, C., & Hsiao, C. D. (2008). Crystal structures of the 70-kDa heat shock proteins in domain disjoining conformation. The Journal of Biological Chemistry, 283, 15502–15511.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Ciechanover, A., & Kwon, Y. T. (2017). Protein quality control by molecular chaperones in neurodegeneration. Frontiers in Neuroscience, 11, 185.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Clerico, E. M., Tilitsky, J. M., Meng, W., & Gierasch, L. M. (2015). How hsp70 molecular machines interact with their substrates to mediate diverse physiological functions. Journal of Molecular Biology, 427, 1575–1588.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Conz, C., Otto, H., Peisker, K., et al. (2007). Functional characterization of the atypical Hsp70 subunit of yeast ribosome-associated complex. The Journal of Biological Chemistry, 282, 33977–33984.PubMedCrossRefGoogle Scholar
  15. Delewski, W., Paterkiewicz, B., Manicki, M., et al. (2016). Iron-sulfur cluster biogenesis chaperones: Evidence for emergence of mutational robustness of a highly specific protein-protein interaction. Molecular Biology and Evolution, 33, 643–656.PubMedCrossRefGoogle Scholar
  16. Deloche, O., Kelley, W. L., & Georgopoulos, C. (1997). Structure-function analyses of the Ssc1p, Mdj1p, and Mge1p Saccharomyces Cerevisiae mitochondrial proteins in Escherichia Coli. Journal of Bacteriology, 179, 6066–6075.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Dong, M., Bridges, J. P., Apsley, K., Xu, Y., & Weaver, T. E. (2008). ERdj4 and ERdj5 are required for endoplasmic reticulum-associated protein degradation of misfolded surfactant protein C. Molecular Biology of the Cell, 19, 2620–2630.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Doong, H., Rizzo, K., Fang, S., Kulpa, V., Weissman, A. M., & Kohn, E. C. (2003). CAIR-1/BAG-3 abrogates heat shock protein-70 chaperone complex-mediated protein degradation: Accumulation of poly-ubiquitinated Hsp90 client proteins. The Journal of Biological Chemistry, 278, 28490–28500.PubMedCrossRefGoogle Scholar
  19. Doring, K., Ahmed, N., Riemer, T., et al. (2017). Profiling Ssb-nascent chain interactions reveals principles of Hsp70-assisted folding. Cell, 170(298–311), e20.Google Scholar
  20. Duchniewicz, M., Germaniuk, A., Westermann, B., Neupert, W., Schwarz, E., & Marszalek, J. (1999). Dual role of the mitochondrial chaperone Mdj1p in inheritance of mitochondrial DNA in yeast. Molecular and Cellular Biology, 19, 8201–8210.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Dudek, J., Pfeffer, S., Lee, P. H., et al. (2015). Protein transport into the human endoplasmic reticulum. Journal of Molecular Biology, 427, 1159–1175.PubMedCrossRefGoogle Scholar
  22. Dutkiewicz, R., Schilke, B., Knieszner, H., Walter, W., Craig, E. A., & Marszalek, J. (2003). Ssq1, a mitochondrial Hsp70 involved in iron-sulfur (Fe/S) center biogenesis. Similarities to and differences from its bacterial counterpart. The Journal of Biological Chemistry, 278, 29719–29727.PubMedCrossRefGoogle Scholar
  23. Edkins, A. L. (2015). CHIP: A co-chaperone for degradation by the proteasome. Sub-Cellular Biochemistry, 78, 219–242.PubMedCrossRefGoogle Scholar
  24. Elliott, E., Tsvetkov, P., & Ginzburg, I. (2007). BAG-1 associates with Hsc70.Tau complex and regulates the proteasomal degradation of tau protein. The Journal of Biological Chemistry, 282, 37276–37284.PubMedCrossRefGoogle Scholar
  25. Elsner, S., Simian, D., Iosefson, O., Marom, M., & Azem, A. (2009). The mitochondrial protein translocation motor: Structural conservation between the human and yeast Tim14/Pam18-Tim16/Pam16 co-chaperones. International Journal of Molecular Sciences, 10, 2041–2053.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Fan, C. Y., Lee, S., & Cyr, D. M. (2003). Mechanisms for regulation of Hsp70 function by Hsp40. Cell Stress & Chaperones, 8, 309–316.CrossRefGoogle Scholar
  27. Foufelle, F., & Ferre, P. (2007). Unfolded protein response: Its role in physiology and physiopathology. Medical Science (Paris), 23, 291–296.CrossRefGoogle Scholar
  28. Frazier, A. E., Dudek, J., Guiard, B., et al. (2004). Pam16 has an essential role in the mitochondrial protein import motor. Nature Structural & Molecular Biology, 11, 226–233.CrossRefGoogle Scholar
  29. Gardner, B. M., Pincus, D., Gotthardt, K., Gallagher, C. M., & Walter, P. (2013). Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harbor Perspectives in Biology, 5, a013169.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Gautschi, M., Lilie, H., Funfschilling, U. et al. (2001). RAC, a stable ribosome-associated complex in yeast formed by the DnaK-DnaJ homologs Ssz1p and zuotin. Proceedings of the National Academy of Sciences of the United States of America 98, 3762–3767.CrossRefGoogle Scholar
  31. Gautschi, M., Mun, A., Ross, S., Rospert, S. (2002). A functional chaperone triad on the yeast ribosome. Proceedings of the National Academy of Sciences of the United States of America 99, 4209–4214.CrossRefGoogle Scholar
  32. Gething, M. J. (1999). Role and regulation of the ER chaperone BiP. Seminars in Cell & Developmental Biology, 10, 465–472.CrossRefGoogle Scholar
  33. Glick, B. S. (1995). Pathways and energetics of mitochondrial protein import in Saccharomyces Cerevisiae. Methods in Enzymology, 260, 224–231.PubMedCrossRefGoogle Scholar
  34. Goswami, A. V., Chittoor, B., & D'Silva, P. (2010). Understanding the functional interplay between mammalian mitochondrial Hsp70 chaperone machine components. The Journal of Biological Chemistry, 285, 19472–19482.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Gumiero, A., Conz, C., Gese, G. V., et al. (2016). Interaction of the cotranslational Hsp70 Ssb with ribosomal proteins and rRNA depends on its lid domain. Nature Communications, 7, 13563.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Ham, H., Woolery, A. R., Tracy, C., Stenesen, D., Kramer, H., & Orth, K. (2014). Unfolded protein response-regulated drosophila fic (dFic) protein reversibly AMPylates BiP chaperone during endoplasmic reticulum homeostasis. The Journal of Biological Chemistry, 289, 36059–36069.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Hartl, F. U., & Hayer-Hartl, M. (2009). Converging concepts of protein folding in vitro and in vivo. Nature Structural & Molecular Biology, 16, 574–581.CrossRefGoogle Scholar
  38. Hartl, F. U., Bracher, A., & Hayer-Hartl, M. (2011). Molecular chaperones in protein folding and proteostasis. Nature, 475, 324–332.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Hassdenteufel, S., Klein, M. C., Melnyk, A., & Zimmermann, R. (2014). Protein transport into the human ER and related diseases, Sec61-channelopathies. Biochemistry and Cell Biology, 92, 499–509.PubMedCrossRefGoogle Scholar
  40. Hendershot, L. M. (2004). The ER function BiP is a master regulator of ER function. Mount Sinai Journal of Medicine, 71, 289–297.PubMedGoogle Scholar
  41. Huang, P., Gautschi, M., Walter, W., Rospert, S., & Craig, E. A. (2005). The Hsp70 Ssz1 modulates the function of the ribosome-associated J-protein Zuo1. Nature Structural & Molecular Biology, 12, 497–504.CrossRefGoogle Scholar
  42. Hubscher, V., Mudholkar, K., & Rospert, S. (2017). The yeast Hsp70 homolog Ssb: A chaperone for general de novo protein folding and a nanny for specific intrinsically disordered protein domains. Current Genetics, 63, 9–13.PubMedCrossRefGoogle Scholar
  43. Jacob, J. A., Salmani, J. M. M., Jiang, Z., et al. (2017). Autophagy: An overview and its roles in cancer and obesity. Clinica Chimica Acta, 468, 85–89.CrossRefGoogle Scholar
  44. Ji, C. H., & Kwon, Y. T. (2017). Crosstalk and interplay between the ubiquitin-proteasome system and autophagy. Molecules and Cells, 40, 441–449.PubMedPubMedCentralGoogle Scholar
  45. Jin, Y., Awad, W., Petrova, K., & Hendershot, L. M. (2008). Regulated release of ERdj3 from unfolded proteins by BiP. The EMBO Journal, 27, 2873–2882.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Kahali, S., Sarcar, B., Fang, B., et al. (2010). Activation of the unfolded protein response contributes toward the antitumor activity of vorinostat. Neoplasia, 12, 80–86.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Kampinga, H. H., & Craig, E. A. (2010). The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nature Reviews. Molecular Cell Biology, 11, 579–592.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Kania, E., Pajak, B., & Orzechowski, A. (2015). Calcium homeostasis and ER stress in control of autophagy in cancer cells. BioMed Research International, 352794.Google Scholar
  49. Kaushik, S., & Cuervo, A. M. (2012). Chaperone-mediated autophagy: A unique way to enter the lysosome world. Trends in Cell Biology, 22, 407–417.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Kettern, N., Dreiseidler, M., Tawo, R., & Hohfeld, J. (2010). Chaperone-assisted degradation: Multiple paths to destruction. Biological Chemistry, 391, 481–489.PubMedCrossRefGoogle Scholar
  51. Kim, R., Saxena, S., Gordon, D. M., Pain, D., & Dancis, A. (2001). J-domain protein, Jac1p, of yeast mitochondria required for iron homeostasis and activity of Fe-S cluster proteins. The Journal of Biological Chemistry, 276, 17524–17532.PubMedCrossRefGoogle Scholar
  52. Kityk, R., Kopp, J., Sinning, I., & Mayer, M. P. (2012). Structure and dynamics of the ATP-bound open conformation of Hsp70 chaperones. Molecular Cell, 48, 863–874.PubMedCrossRefGoogle Scholar
  53. Koplin, A., Preissler, S., Ilina, Y., et al. (2010). A dual function for chaperones SSB-RAC and the NAC nascent polypeptide-associated complex on ribosomes. The Journal of Cell Biology, 189, 57–68.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Korennykh, A., & Walter, P. (2012). Structural basis of the unfolded protein response. Annual Review of Cell and Developmental Biology, 28, 251–277.PubMedCrossRefGoogle Scholar
  55. Kozany, C., Mokranjac, D., Sichting, M., Neupert, W., & Hell, K. (2004). The J domain-related cochaperone Tim16 is a constituent of the mitochondrial TIM23 preprotein translocase. Nature Structural & Molecular Biology, 11, 234–241.CrossRefGoogle Scholar
  56. Kronidou, N.G., Oppliger, W., Bolliger, L. et al. (1994). Dynamic interaction between Isp45 and mitochondrial hsp70 in the protein import system of the yeast mitochondrial inner membrane. Proceedings of the National Academy of Sciences of the United States of America. 91, 12818–12822.CrossRefGoogle Scholar
  57. Kutik, S., Stroud, D. A., Wiedemann, N., & Pfanner, N. (2009). Evolution of mitochondrial protein biogenesis. Biochimica et Biophysica Acta, 1790, 409–415.PubMedCrossRefGoogle Scholar
  58. Lai, A. L., Clerico, E. M., Blackburn, M. E., et al. (2017). Key features of an Hsp70 chaperone allosteric landscape revealed by ion-mobility native mass spectrometry and double electron-electron resonance. The Journal of Biological Chemistry, 292, 8773–8785.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Laloraya, S., Gambill, B.D., Craig, E.A. (1994). A role for a eukaryotic GrpE-related protein, Mge1p, in protein translocation. Proceedings of the National Academy of Sciences of the United States of America 91, 6481–6485.CrossRefGoogle Scholar
  60. Leidig, C., Bange, G., Kopp, J., et al. (2013). Structural characterization of a eukaryotic chaperone--the ribosome-associated complex. Nature Structural & Molecular Biology, 20, 23–28.CrossRefGoogle Scholar
  61. Lewy, T. G., Grabowski, J. M., & Bloom, M. E. (2017). BiP: Master regulator of the unfolded protein response and crucial factor in Flavivirus biology. The Yale Journal of Biology and Medicine, 90, 291–300.PubMedPubMedCentralGoogle Scholar
  62. Li, Y., Dudek, J., Guiard, B., Pfanner, N., Rehling, P., & Voos, W. (2004). The presequence translocase-associated protein import motor of mitochondria. Pam16 functions in an antagonistic manner to Pam18. The Journal of Biological Chemistry, 279, 38047–38054.PubMedCrossRefGoogle Scholar
  63. Li, W., Yang, Q., & Mao, Z. (2011). Chaperone-mediated autophagy: Machinery, regulation and biological consequences. Cellular and Molecular Life Sciences, 68, 749–763.PubMedCrossRefGoogle Scholar
  64. Lievremont, J.P., Rizzuto, R., Hendershot,.L., Meldolesi, J. (1997) BiP, a major chaperone protein of the endoplasmic reticulum lumen, plays a direct and important role in the storage of the rapidly exchanging pool of Ca2+. The Journal of Biological Chemistry 272, 30873–30879.PubMedCrossRefGoogle Scholar
  65. Liu, Q., & Hendrickson, W. A. (2007). Insights into Hsp70 chaperone activity from a crystal structure of the yeast Hsp110 Sse1. Cell, 131, 106–120.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Maattanen, P., Gehring, K., Bergeron, J. J., & Thomas, D. Y. (2010). Protein quality control in the ER: The recognition of misfolded proteins. Seminars in Cell & Developmental Biology, 21, 500–511.CrossRefGoogle Scholar
  67. Mapa, K., Sikor, M., Kudryavtsev, V., et al. (2010). The conformational dynamics of the mitochondrial Hsp70 chaperone. Molecular Cell, 38, 89–100.PubMedCrossRefGoogle Scholar
  68. Marcinowski, M., Holler, M., Feige, M. J., Baerend, D., Lamb, D. C., & Buchner, J. (2011). Substrate discrimination of the chaperone BiP by autonomous and cochaperone-regulated conformational transitions. Nature Structural & Molecular Biology, 18, 150–158.CrossRefGoogle Scholar
  69. Massey, A. C., Zhang, C., & Cuervo, A. M. (2006). Chaperone-mediated autophagy in aging and disease. Current Topics in Developmental Biology, 73, 205–235.PubMedCrossRefGoogle Scholar
  70. Matouschek, A., Pfanner, N., & Voos, W. (2000). Protein unfolding by mitochondria. The Hsp70 import motor. EMBO Reports, 1, 404–410.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Mayer, M. P. (2013). Hsp70 chaperone dynamics and molecular mechanism. Trends in Biochemical Sciences, 38, 507–514.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Mayer, M. P., & Bukau, B. (2005). Hsp70 chaperones: Cellular functions and molecular mechanism. Cellular and Molecular Life Sciences, 62, 670–684.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Mayer, M. P., & Kityk, R. (2015). Insights into the molecular mechanism of allostery in Hsp70s. Frontiers in Molecular Biosciences, 2, 58.PubMedPubMedCentralCrossRefGoogle Scholar
  74. McCaffrey, K., & Braakman, I. (2016). Protein quality control at the endoplasmic reticulum. Essays in Biochemistry, 60, 227–235.PubMedCrossRefGoogle Scholar
  75. McDonough, H., & Patterson, C. (2003). CHIP: A link between the chaperone and proteasome systems. Cell Stress & Chaperones, 8, 303–308.CrossRefGoogle Scholar
  76. Miao, B., Davis, J. E., & Craig, E. A. (1997). Mge1 functions as a nucleotide release factor for Ssc1, a mitochondrial Hsp70 of Saccharomyces Cerevisiae. Journal of Molecular Biology, 265, 541–552.PubMedCrossRefGoogle Scholar
  77. Mokranjac, D., Sichting, M., Neupert, W., & Hell, K. (2003). Tim14, a novel key component of the import motor of the TIM23 protein translocase of mitochondria. The EMBO Journal, 22, 4945–4956.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Mokranjac, D., Bourenkov, G., Hell, K., Neupert, W., & Groll, M. (2006). Structure and function of Tim14 and Tim16, the J and J-like components of the mitochondrial protein import motor. The EMBO Journal, 25, 4675–4685.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Neupert, W., & Brunner, M. (2002). The protein import motor of mitochondria. Nature Reviews. Molecular Cell Biology, 3, 555–565.PubMedCrossRefGoogle Scholar
  80. Neupert, W., & Herrmann, J. M. (2007). Translocation of proteins into mitochondria. Annual Review of Biochemistry, 76, 723–749.PubMedCrossRefGoogle Scholar
  81. Okamoto, K., Brinker, A., Paschen, S. A., et al. (2002). The protein import motor of mitochondria: A targeted molecular ratchet driving unfolding and translocation. The EMBO Journal, 21, 3659–3671.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Paul, I., & Ghosh, M. K. (2014). The E3 ligase CHIP: Insights into its structure and regulation. BioMed Research International, 918183.Google Scholar
  83. Peisker, K., Braun, D., Wolfle, T., et al. (2008). Ribosome-associated complex binds to ribosomes in close proximity of Rpl31 at the exit of the polypeptide tunnel in yeast. Molecular Biology of the Cell, 19, 5279–5288.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Polier, S., Dragovic, Z., Hartl, F. U., & Bracher, A. (2008). Structural basis for the cooperation of Hsp70 and Hsp110 chaperones in protein folding. Cell, 133, 1068–1079.PubMedCrossRefGoogle Scholar
  85. Preissler, S., & Deuerling, E. (2012). Ribosome-associated chaperones as key players in proteostasis. Trends in Biochemical Sciences, 37, 274–283.PubMedCrossRefGoogle Scholar
  86. Preissler, S., Chambers, J. E., Crespillo-Casado, A., et al. (2015a). Physiological modulation of BiP activity by trans-protomer engagement of the interdomain linker. eLife, 4, e08961.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Preissler, S., Rato, C., Chen, R., et al. (2015b). AMPylation matches BiP activity to client protein load in the endoplasmic reticulum. eLife, 4, e12621.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Prip-Buus, C., Westerman, B., Schmitt, M., Langer, T., Neupert, W., & Schwarz, E. (1996). Role of the mitochondrial DnaJ homologue, Mdj1p, in the prevention of heat-induced protein aggregation. FEBS Letters, 380, 142–146.PubMedCrossRefGoogle Scholar
  89. Qi, L., & Zhang, X. D. (2014). Role of chaperone-mediated autophagy in degrading Huntington's disease-associated huntingtin protein. Acta Biochimica et Biophysica Sinica Shanghai, 46, 83–91.CrossRefGoogle Scholar
  90. Qi, R., Sarbeng, E. B., Liu, Q., et al. (2013). Allosteric opening of the polypeptide-binding site when an Hsp70 binds ATP. Nature Structural & Molecular Biology, 20(7), 900.CrossRefGoogle Scholar
  91. Rakwalska, M., & Rospert, S. (2004). The ribosome-bound chaperones RAC and Ssb1/2p are required for accurate translation in Saccharomyces Cerevisiae. Molecular and Cellular Biology, 24, 9186–9197.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Rassow, J., Maarse, A. C., Krainer, E., et al. (1994). Mitochondrial protein import: Biochemical and genetic evidence for interaction of matrix hsp70 and the inner membrane protein MIM44. The Journal of Cell Biology, 127, 1547–1556.PubMedCrossRefGoogle Scholar
  93. Rout, A. K., Strub, M. P., Piszczek, G., & Tjandra, N. (2014). Structure of transmembrane domain of lysosome-associated membrane protein type 2a (LAMP-2A) reveals key features for substrate specificity in chaperone-mediated autophagy. The Journal of Biological Chemistry, 289, 35111–35123.PubMedPubMedCentralCrossRefGoogle Scholar
  94. Rowley, N., Prip-Buus, C., Westermann, B., et al. (1994). Mdj1p, a novel chaperone of the DnaJ family, is involved in mitochondrial biogenesis and protein folding. Cell, 77, 249–259.PubMedPubMedCentralCrossRefGoogle Scholar
  95. Rudiger, S., Germeroth, L., Schneider-Mergener, J., & Bukau, B. (1997). Substrate specificity of the DnaK chaperone determined by screening cellulose-bound peptide libraries. The EMBO Journal, 16(7), 1501.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Sakuragi, S., Liu, Q., & Craig, E. (1999). Interaction between the nucleotide exchange factor Mge1 and the mitochondrial Hsp70 Ssc1. The Journal of Biological Chemistry, 274, 11275–11282.PubMedCrossRefGoogle Scholar
  97. Sanjuan Szklarz, L. K., Guiard, B., Rissler, M., et al. (2005). Inactivation of the mitochondrial heat shock protein zim17 leads to aggregation of matrix hsp70s followed by pleiotropic effects on morphology and protein biogenesis. Journal of Molecular Biology, 351, 206–218.PubMedCrossRefGoogle Scholar
  98. Sano, R., & Reed, J. C. (2013). ER stress-induced cell death mechanisms. Biochimica et Biophysica Acta, 1833, 3460–3470.PubMedCrossRefGoogle Scholar
  99. Sanyal, A., Chen, A. J., Nakayasu, E. S., et al. (2015). A novel link between fic (filamentation induced by cAMP)-mediated adenylylation/AMPylation and the unfolded protein response. The Journal of Biological Chemistry, 290, 8482–8499.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Schauble, N., Lang, S., Jung, M., et al. (2012). BiP-mediated closing of the Sec61 channel limits Ca2+ leakage from the ER. The EMBO Journal, 31, 3282–3296.PubMedPubMedCentralCrossRefGoogle Scholar
  101. Schilke, B., Williams, B., Knieszner, H., et al. (2006). Evolution of mitochondrial chaperones utilized in Fe-S cluster biogenesis. Current Biology, 16, 1660–1665.PubMedCrossRefGoogle Scholar
  102. Schmidt, S., Strub, A., Rottgers, K., Zufall, N., & Voos, W. (2001). The two mitochondrial heat shock proteins 70, Ssc1 and Ssq1, compete for the cochaperone Mge1. Journal of Molecular Biology, 313, 13–26.PubMedCrossRefGoogle Scholar
  103. Schneider, H. C., Berthold, J., Bauer, M. F., et al. (1994). Mitochondrial Hsp70/MIM44 complex facilitates protein import. Nature, 371, 768–774.PubMedCrossRefGoogle Scholar
  104. Shen, Y., & Hendershot, L. M. (2005). ERdj3, a stress-inducible endoplasmic reticulum DnaJ homologue, serves as a cofactor for BiP's interactions with unfolded substrates. Molecular Biology of the Cell, 16, 40–50.PubMedPubMedCentralCrossRefGoogle Scholar
  105. Sichting, M., Mokranjac, D., Azem, A., Neupert, W., & Hell, K. (2005). Maintenance of structure and function of mitochondrial Hsp70 chaperones requires the chaperone Hep1. The EMBO Journal, 24, 1046–1056.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Sikor, M., Mapa, K., von Voithenberg, L. V., Mokranjac, D., & Lamb, D. C. (2013). Real-time observation of the conformational dynamics of mitochondrial Hsp70 by spFRET. The EMBO Journal, 32, 1639–1649.PubMedPubMedCentralCrossRefGoogle Scholar
  107. Swain, J. F., Dinler, G., Sivendran, R., Montgomery, D. L., Stotz, M., & Gierasch, L. M. (2007). Hsp70 chaperone ligands control domain association via an allosteric mechanism mediated by the interdomain linker. Molecular Cell, 26, 27–39.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Truscott, K. N., Voos, W., Frazier, A. E., et al. (2003). A J-protein is an essential subunit of the presequence translocase-associated protein import motor of mitochondria. The Journal of Cell Biology, 163, 707–713.PubMedPubMedCentralCrossRefGoogle Scholar
  109. Ungermann, C., Neupert, W., & Cyr, D. M. (1994). The role of Hsp70 in conferring unidirectionality on protein translocation into mitochondria. Science, 266, 1250–1253.PubMedCrossRefGoogle Scholar
  110. Voisine, C., Cheng, Y.C., Ohlson, M. et al. (2001). Jac1, a mitochondrial J-type chaperone, is involved in the biogenesis of Fe/S clusters in Saccharomyces Cerevisiae. Proceedings of the National Academy of Sciences of the United States of America 98, 1483–1488.CrossRefGoogle Scholar
  111. von Ahsen, O., Voos, W., Henninger, H., & Pfanner, N. (1995). The mitochondrial protein import machinery. Role of ATP in dissociation of the Hsp70.Mim44 complex. The Journal of Biological Chemistry, 270, 29848–29853.CrossRefGoogle Scholar
  112. Voos, W., & Rottgers, K. (2002). Molecular chaperones as essential mediators of mitochondrial biogenesis. Biochimica et Biophysica Acta, 1592, 51–62.PubMedCrossRefGoogle Scholar
  113. Walter, P., & Ron, D. (2011). The unfolded protein response: From stress pathway to homeostatic regulation. Science, 334, 1081–1086.PubMedCrossRefPubMedCentralGoogle Scholar
  114. Wang, J., Lee, J., Liem, D., & Ping, P. (2017). HSPA5 gene encoding Hsp70 chaperone BiP in the endoplasmic reticulum. Gene, 618, 14–23.PubMedCrossRefPubMedCentralGoogle Scholar
  115. Westermann, B., Gaume, B., Herrmann, J. M., Neupert, W., & Schwarz, E. (1996). Role of the mitochondrial DnaJ homolog Mdj1p as a chaperone for mitochondrially synthesized and imported proteins. Molecular and Cellular Biology, 16, 7063–7071.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Wiedemann, N., & Pfanner, N. (2017). Mitochondrial machineries for protein import and assembly. Annual Review of Biochemistry, 86, 685–714.PubMedCrossRefGoogle Scholar
  117. Willmund, F., del Alamo, M., Pechmann, S., et al. (2013). The cotranslational function of ribosome-associated Hsp70 in eukaryotic protein homeostasis. Cell, 152, 196–209.PubMedPubMedCentralCrossRefGoogle Scholar
  118. Yamamoto, H., Momose, T., Yatsukawa, Y., et al. (2005). Identification of a novel member of yeast mitochondrial Hsp70-associated motor and chaperone proteins that facilitates protein translocation across the inner membrane. FEBS Letters, 579, 507–511.PubMedCrossRefGoogle Scholar
  119. Yang, J., Nune, M., Zong, Y., Zhou, L., & Liu, Q. (2015). Close and allosteric opening of the polypeptide-binding site in a human Hsp70 chaperone BiP. Structure, 23, 2191–2203.PubMedPubMedCentralCrossRefGoogle Scholar
  120. Zhu, X., Zhao, X., Burkholder, W. F., et al. (1996). Structural analysis of substrate binding by the molecular chaperone DnaK. Science, 272, 1606–1614.PubMedPubMedCentralCrossRefGoogle Scholar
  121. Zhuravleva, A., Clerico, E. M., & Gierasch, L. M. (2012). An interdomain energetic tug-of-war creates the allosterically active state in Hsp70 molecular chaperones. Cell, 151, 1296–1307.PubMedPubMedCentralCrossRefGoogle Scholar
  122. Zimmermann, R., Eyrisch, S., Ahmad, M., & Helms, V. (2011). Protein translocation across the ER membrane. Biochimica et Biophysica Acta, 1808, 912–924.PubMedCrossRefGoogle Scholar
  123. Zuiderweg, E. R., Bertelsen, E. B., Rousaki, A., Mayer, M. P., Gestwicki, J. E., & Ahmad, A. (2013). Allostery in the Hsp70 chaperone proteins. Topics in Current Chemistry, 328, 99–153.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Hepatitis DivisionNational Institute of VirologyPashanIndia
  2. 2.Department of Life Sciences, School of Natural SciencesShiv Nadar UniversityGreater NoidaIndia

Personalised recommendations