Skip to main content
SpringerLink
Log in

The 70 KDA Heat Shock Protein Hsp70 as Part of a Protein Disaggregase System

  • Chapter
  • First Online:
Book cover Regulation of Heat Shock Protein Responses

Part of the book series: Heat Shock Proteins ((HESP,volume 13))

Abstract

Proteins participate in a wide variety of cellular functions, which enable many activities in our body. However, proteins need to reach their correct state of folding to function properly. In the cell, the folding of many nascent proteins is aided by the 70 kDa heat shock protein (Hsp70). When folding is not favorable, misfolded species accumulate leading to the formation of aggregates, which leads to loss of function and is the basis of several diseases. In addition to its function of aiding folding, Hsp70 is also an important agent in disaggregation, sometimes acting in a bichaperone system together with Hsp100 in several organisms, such as bacteria, fungi and plants. Surprisingly, animals lack a bonafide Hsp100 orthologue. To overcome this limitation, animals evolved a Hsp70-based disaggregation system, in which Hsp70 cooperates with Hsp40 and Hsp110 co-chaperones to reactivate aggregated substrates. This chapter revises the most recent models for the mechanism of interaction between these proteins and how they cooperate to solubilize protein aggregates.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abrahão, J., Mokry, D. Z., & Ramos, C. H. (2017). Hsp78 (78 kDa heat shock protein), a representative AAA family member found in the mitochondrial matrix of Saccharomyces Cerevisiae. Mini review article. Frontiers in Molecular Biosciences, 4, 60.

    Article  PubMed  PubMed Central  Google Scholar 

  • Abu-Hamad, S., Kahn, J., Leyton-Jaimes, M. F., Rosenblatt, J., & Israelson, A. (2017). Misfolded SOD1 accumulation and mitochondrial association contribute to the selective vulnerability of motor neurons in familial ALS: Correlation to human disease. ACS Chemical Neuroscience, 8(10), 2225–2234.

    Article  CAS  PubMed  Google Scholar 

  • Aguado, A., Fernandez-Higuero, J. A., Moro, F., & Muga, A. (2015). Chaperone-assisted protein aggregate reactivation: Different solutions for the same problem. Archives of Biochemistry and Biophysics, 580, 121–134.

    Article  CAS  PubMed  Google Scholar 

  • Akiyama, H., Kondo, H., Arai, T., Ikeda, K., Kato, M., Iseki, E., Schwab, C., & McGeer, P. L. (2004). Expression of BRI, the normal precursor of the amyloid protein of familial British dementia, in human brain. Acta Neuropathologica, 107, 53–58.

    Article  CAS  PubMed  Google Scholar 

  • Alderson, T. R., Kim, J. H., & Markley, J. L. (2016). Dynamical structures of Hsp70 and Hsp70-Hsp40 complexes. Structure (London, England), 24, 1014–1030.

    Article  CAS  Google Scholar 

  • Alzheimer’s Association. (2016). 2016 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia, 12, 459–509.

    Article  Google Scholar 

  • Anderson, J. F., Siller, E., & Barral, J. M. (2011). Disorders of protein biogenesis and stability. Protein and Peptide Letters, 18, 110–121.

    Article  CAS  PubMed  Google Scholar 

  • Andreasson, C., Fiaux, J., Rampelt, H., Druffel-Augustin, S., & Bukau, B. (2008a). Insights into the structural dynamics of the Hsp110-Hsp70 interaction reveal the mechanism for nucleotide exchange activity. Proceedings of the National Academy of Sciences of the United States of America, 105, 16519–16524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andreasson, C., Fiaux, J., Rampelt, H., Mayer, M. P., & Bukau, B. (2008b). Hsp110 is a nucleotide-activated exchange factor for Hsp70. The Journal of Biological Chemistry, 283, 8877–8884.

    Article  CAS  PubMed  Google Scholar 

  • Finka, A., Sharma, S. K., & Goloubinoff, P. (2015). Multi-layered molecular mechanisms of polypeptide holding, unfolding and disaggregation by HSP70/HSP110 chaperones. Frontiers in Molecular Biosciences, 2, 29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Balch, W. E., Morimoto, R. I., Dillin, A., & Kelly, J. W. (2008). Adapting proteostasis for disease intervention. Science (New York, N.Y.), 319, 916–919.

    Article  CAS  Google Scholar 

  • Barends, T. R. M., Werbeck, N. D., & Reinstein, J. (2010). Disaggregases in 4 dimensions. Current Opinion in Structural Biology, 20, 46–53.

    Article  CAS  PubMed  Google Scholar 

  • Beinker, P., Schlee, S., Groemping, Y., Seidel, R., & Reinstein, J. (2002). The N terminus of ClpB from Thermus thermophilus is not essential for the chaperone activity. The Journal of Biological Chemistry, 277, 47160–47166.

    Article  CAS  PubMed  Google Scholar 

  • Bhandari, V., & Houry, W. A. (2015). Substrate interaction networks of the Escherichia coli chaperones: Trigger factor, DnaK and GroEL. Advances in Experimental Medicine and Biology, 883, 271–294.

    Article  CAS  PubMed  Google Scholar 

  • Borges, J. C., Fischer, H., Craievich, A. F., & Ramos, C. H. I. (2005). Low resolution structural study of two human HSP40 chaperones in solution. DJA1 from subfamily a and DJB4 from subfamily B have different quaternary structures. The Journal of Biological Chemistry, 280, 13671–13681.

    Article  CAS  PubMed  Google Scholar 

  • Borges, J. C., & Ramos, C. H. I. (2005). Protein folding assisted by chaperones. Protein and Peptide Letters, 12, 257–261.

    Article  CAS  PubMed  Google Scholar 

  • Borges, J. C., & Ramos, C. H. I. (2006). Spectroscopic and thermodynamic measurements of nucleotide-induced changes in the human 70-kDa heat shock cognate protein. Archives of Biochemistry and Biophysics, 452, 46–54.

    Article  CAS  PubMed  Google Scholar 

  • Calamini, B., & Morimoto, R. I. (2012). Protein homeostasis as a therapeutic target for diseases of protein conformation. Current Topics in Medicinal Chemistry, 12, 2623–2640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carroni, M., Kummer, E., Oguchi, Y., Wendler, P., Clare, D. K., Sinning, I., Kopp, J., Mogk, A., Bukau, B., & Saibil, H. R. (2014). Head-to-tail interactions of the coiled-coil domains regulate ClpB activity and cooperation with Hsp70 in protein disaggregation. eLife, 3, e02481.

    Article  PubMed  PubMed Central  Google Scholar 

  • Castellano, L. M., & Shorter, J. (2012). The surprising role of amyloid fibrils in HIV infection. Biology, 1, 58–80.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chaudhuri, T. K., & Paul, S. (2006). Protein-misfolding diseases and chaperone-based therapeutic approaches. The FEBS Journal, 273, 1331–1349.

    Article  CAS  PubMed  Google Scholar 

  • Cheetham, M. E., & Caplan, A. J. (1998). Structure, function and evolution of DnaJ: Conservation and adaptation of chaperone function. Cell Stress & Chaperones, 3, 28–36.

    Article  CAS  Google Scholar 

  • Cheng, S. H., Gregory, R. J., Marshall, J., Paul, S., Souza, D. W., White, G. A., O’Riordan, C. R., & Smith, A. E. (1990). Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell, 63, 827–834.

    Article  CAS  PubMed  Google Scholar 

  • Chiti, F., & Dobson, C. M. (2006). Protein misfolding, functional amyloid, and human disease. Annual Review of Biochemistry, 75, 333–366.

    Article  CAS  PubMed  Google Scholar 

  • Chiti, F., & Dobson, C. M. (2017). Protein Misfolding, amyloid formation, and human disease: A summary of progress over the last decade. Annual Review of Biochemistry, 86, 27–68.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collier, T. J., Srivastava, K. R., Justman, C., Grammatopoulous, T., Hutter-Paier, B., Prokesch, M., Havas, D., Rochet, J. C., Lui, F., Jock, K., de Oliveira, P., Stirtz, G. L., Dettermer, U., Sortweel, C. E., Feany, M. B., Lansbury, P., Lapidus, L., & Paumier, K. L. (2017). Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form. Neurobiology of Disease, 106, 191–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cuanalo-Contreras, K., Mukherjee, A., & Soto, C. (2013). Role of protein misfolding and proteostasis deficiency in protein misfolding diseases and aging. International Journal of Cell Biology, 2013, 638083.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cyr, D. M., Langer, T., & Douglas, M. G. (1994). DnaJ-like proteins: Molecular chaperones and specific regulators of Hsp70. Trends in Biochemical Sciences, 19, 176–181.

    Article  CAS  PubMed  Google Scholar 

  • Cyr, D. M., & Ramos, C. H. I. (2015). Specification of Hsp70 function by Type I and Type II Hsp40. In G. Blatch & A. L. Edkins (Eds.), The networking of chaperones by co-chaperones, subcellular biochemistry (Vol. 78, pp. 91–102). Cham: Springer International Publishing.

    Google Scholar 

  • da Silva, K. P., & Borges, J. C. (2011). The molecular chaperone Hsp70 family members function by a bidirectional heterotrophic allosteric mechanism. Protein and Peptide Letters, 18, 132–142.

    Article  PubMed  Google Scholar 

  • De Felice, F. G., Lourenco, M. V., & Ferreira, S. T. (2014). How does brain insulin resistance develop in Alzheimer’s disease? Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 10, S26–S32.

    Article  Google Scholar 

  • De Maio, A. (2014). Extracellular Hsp70: Export and function. Current Protein & Peptide Science, 15, 225–231.

    Article  CAS  Google Scholar 

  • Deane, C. A. S., & Brown, I. R. (2017). Differential targeting of Hsp70 heat shock proteins HSPA6 and HSPA1A with components of a protein disaggregation/refolding machine in differentiated human neuronal cells following thermal stress. Frontiers in Neuroscience, 11, 227.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dekker, S. L., Kampinga, H. H., & Bergink, S. (2015). DNAJs: More than substrate delivery to HSPA. Frontiers in Molecular Biosciences, 2(35).

    Google Scholar 

  • DeSantis, M. E., Leung, E. H., Sweeny, E. A., Jackrel, M. E., Cushman-Nick, M., Neuhaus-Follini, A., Vashist, S., Sochor, M. A., Knight, M. N., & Shorter, J. (2012). Operational plasticity enables hsp104 to disaggregate diverse amyloid and nonamyloid clients. Cell, 151, 778–793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Desantis, M. E., & Shorter, J. (2012). The elusive middle domain of Hsp104 and ClpB: Location and function. Biochimica et Biophysica Acta, 1823, 29–39.

    Article  CAS  PubMed  Google Scholar 

  • Douglas, P. M., & Dillin, A. (2010). Protein homeostasis and aging in neurodegeneration. The Journal of Cell Biology, 190, 719–729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doyle, S. M., Genest, O., & Wickner, S. (2013). Protein rescue from aggregates by powerful molecular chaperone machines. Nature Reviews Molecular Cell Biology, 14, 617–629.

    Article  CAS  PubMed  Google Scholar 

  • Doyle, S. M., Hoskins, J. R., & Wickner, S. (2007). Collaboration between the ClpB AAA+ remodeling protein and the DnaK chaperone system. Proceedings of the National Academy of Sciences of the United States of America, 104, 11138–11144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dragovic, Z., Broadley, S. A., Shomura, Y., Bracher, A., & Hartl, F. U. (2006). Molecular chaperones of the Hsp110 family act as nucleotide exchange factors of Hsp70s. The EMBO Journal, 25, 2519–2528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dubnikov, T., Ben-Gedalya, T., & Cohen, E. (2017). Protein quality control in health and disease. Cold Spring Harbor Perspectives in Biology, 2017(9), a023523.

    Article  CAS  Google Scholar 

  • Duennwald, M. L., Echeverria, A., & Shorter, J. (2012). Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans. PLoS Biology, 10, e1001346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duncan, E. J., Cheetham, M. E., Chapple, J. P., & van der Spuy, J. (2015). The role of HSP70 and its co-chaperones in protein misfolding, aggregation and disease. Sub-Cellular Biochemistry, 78, 243–273.

    Article  CAS  PubMed  Google Scholar 

  • Ebrahimi-Fakhari, D., Wahlster, L., & McLean, P. J. (2012). Protein degradation pathways in Parkinson’s disease – Curse or blessing. Acta Neuropathologica, 124, 153–172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Erzberger, J. P., & Berger, J. M. (2006). Evolutionary relationships and structural mechanisms of AAA+ proteins. Annual Review of Biophysics and Biomolecular Structure, 35, 93–114.

    Article  CAS  PubMed  Google Scholar 

  • Fan, J. Q., & Ishii, S. (2007). Active-site-specific chaperone therapy for Fabry disease. Yin and Yang of enzyme inhibitors. FEBS Journal, 274, 4962–4971.

    Article  CAS  Google Scholar 

  • Foguel, D., & Silva, J. L. (2004). New insights into the mechanisms of protein misfolding and aggregation in amyloidogenic diseases derived from pressure studies. Biochemistry, 43, 11361–11370.

    Article  CAS  PubMed  Google Scholar 

  • Gao, X., Carroni, M., Nussbaum-Krammer, C., Mogk, A., Nillegoda, N. B., Szlachcic, A., Guilbride, D. L., Saibil, H. R., Mayer, M. P., & Bukau, B. (2015). Human Hsp70 Disaggregase reverses Parkinson’s-linked alpha-Synuclein amyloid fibrils. Molecular Cell, 59, 781–793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gates, S. N., Yokom, A. L., Lin, J., Jackrel, M. E., Rizo, A. N., Kendsersky, N. M., Buell, C. E., Sweeny, E. A., Mack, K. L., Chuang, E., Torrente, M. P., Su, M., Shorter, J., & Southworth, D. R. (2017). Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104. Science (New York, NY), 357, 273–279.

    Article  CAS  Google Scholar 

  • Glover, J. R., & Lindquist, S. (1998). Hsp104, Hsp70, and Hsp40: A novel chaperone system that rescues previously aggregated proteins. Cell, 94, 73–82.

    Article  CAS  PubMed  Google Scholar 

  • Goeckeler, J. L., Petruso, A. P., Aguirre, J., Clement, C. C., Chiosis, G., & Brodsky, J. L. (2008). The yeast Hsp110, Sse1p, exhibits high-affinity peptide binding. FEBS Letters, 582, 2393–2396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goloubinoff, P. (2016). Mechanisms of protein homeostasis in health, aging and disease. Swiss Medical Weekly, 146, w14306.

    PubMed  Google Scholar 

  • Goloubinoff, P., Mogk, A., Zvi, A. P., Tomoyasu, T., & Bukau, B. (1999). Sequential mechanism of solubilization and refolding of stable protein aggregates by a bichaperone network. Proceedings of the National Academy of Sciences of the United States of America, 96, 13732–13737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonçalves, C. C., & Ramos, C. H. I. (2016). Molecular Chaperones and HSPs in Sugarcane and Eucalyptus. In A. Asea, P. Kaur, & S. Calderwood (Eds.), Heat Shock Proteins and Plants (Vol. 10, pp. 245–283). Cham: Springer International Publishing.

    Chapter  Google Scholar 

  • Hardy, J., & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science (New York, N.Y.), 297, 353–356.

    Article  CAS  Google Scholar 

  • Hinault, M. P., Cuendet, A. F., Mattoo, R. U., Mensi, M., Dietler, G., Lashuel, H. A., & Goloubinoff, P. (2010). Stable alpha-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones. The Journal of Biological Chemistry, 285, 38173–38182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hipp, M. S., Park, S. H., & Hartl, F. U. (2014). Proteostasis impairment in protein-misfolding and -aggregation diseases. Trends in Cell Biology, 24, 506–514.

    Article  CAS  PubMed  Google Scholar 

  • Holmes, W. M., Klaips, C. L., & Serio, T. R. (2014). Defining the limits: Protein aggregation and toxicity in vivo. Critical Reviews in Biochemistry and Molecular Biology, 49, 294–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoogstra-Berends, F., Meijering, R. A., Zhang, D., Heeres, A., Loen, L., Seerden, J. P., Kuipers, I., Kampinga, H. H., Henning, R. H., & Brundel, B. J. (2012). Heat shock protein-inducing compounds as therapeutics to restore proteostasis in atrial fibrillation. Trends in Cardiovascular Medicine, 22, 62–68.

    Article  CAS  PubMed  Google Scholar 

  • Jackrel, M. E., DeSantis, M. E., Martinez, B. A., Castellano, L. M., Stewart, R. M., Caldwell, K. A., Caldwell, G. A., & Shorter, J. (2014). Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell, 156, 170–182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jeng, W., Lee, S., Sung, N., Lee, J., & Tsai, F. T. (2015). Molecular chaperones: Guardians of the proteome in normal and disease states. F1000Research, 4, 1448.

    Google Scholar 

  • Johnson, S. M., Connelly, S., Fearns, C., Powers, E. T., & Kelly, J. W. (2012). The transthyretin amyloidoses: From delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. Journal of Molecular Biology, 421, 185–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaushik, S., & Cuervo, A. M. (2015). Proteostasis and aging. Nature Medicine, 21, 1406–1415.

    Article  CAS  PubMed  Google Scholar 

  • Knowles, T. P., Vendruscolo, M., & Dobson, C. M. (2014). The amyloid state and its association with protein misfolding diseases. Nature Reviews Molecular Cell Biology, 15, 384–396.

    Article  CAS  PubMed  Google Scholar 

  • Labbadia, J., & Morimoto, R. I. (2015). The biology of proteostasis in aging and disease. Annual Review of Biochemistry, 84, 435–464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee, J., Kim, J. H., Biter, A. B., Sielaff, B., Lee, S., & Tsai, F. T. (2013). Heat shock protein (Hsp) 70 is an activator of the Hsp104 motor. Proceedings of the National Academy of Sciences of the United States of America, 110, 8513–8518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee, S., Sowa, M. E., Watanabe, Y. H., Sigler, P. B., Chiu, W., Yoshida, M., & Tsai, F. T. (2003). The structure of ClpB: A molecular chaperone that rescues proteins from an aggregated state. Cell, 115, 229–240.

    Article  CAS  PubMed  Google Scholar 

  • Li, J., Wu, Y., Qian, X., & Sha, B. (2006). Crystal structure of yeast Sis1 peptide-binding fragment and Hsp70 Ssa1 C-terminal complex. The Biochemical Journal, 398, 353–360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, X., Shao, H., Taylor, I. R., & Gestwicki, J. E. (2016). Targeting allosteric control mechanisms in heat shock protein 70 (Hsp70). Current Topics in Medicinal Chemistry, 16, 2729–2740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lo Bianco, C., Shorter, J., Regulier, E., Lashuel, H., Iwatsubo, T., Lindquist, S., & Aebischer, P. (2008). Hsp104 antagonizes alpha-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease. The Journal of Clinical Investigation, 118, 3087–3097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lv, T., Li, X., Zhang, W., Zhao, X., Ou, X., & Huang, J. (2016). Recent advance in the molecular genetics of Wilson disease and hereditary hemochromatosis. European Journal of Medical Genetics, 59, 532–539.

    Article  PubMed  Google Scholar 

  • Macario, A. J., & Conway de Macario, E. (2000). Stress and molecular chaperones in disease. International Journal of Clinical & Laboratory Research, 30, 49–66.

    Article  CAS  Google Scholar 

  • Mack, K. L., & Shorter, J. (2016). Engineering and evolution of molecular chaperones and protein Disaggregases with enhanced activity. Frontiers in Molecular Biosciences, 3, 8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mackay, R. G., Helsen, C. W., Tkach, J. M., & Glover, J. R. (2008). The C-terminal extension of Saccharomyces Cerevisiae Hsp104 plays a role in oligomer assembly. Biochemistry, 47, 1918–1927.

    Article  CAS  PubMed  Google Scholar 

  • Mattoo, R. U., Sharma, S. K., Priya, S., Finka, A., & Goloubinoff, P. (2013). Hsp110 is a bona fide chaperone using ATP to unfold stable misfolded polypeptides and reciprocally collaborate with Hsp70 to solubilize protein aggregates. The Journal of Biological Chemistry, 288, 21399–21411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayer, M. P. (2010). Gymnastics of molecular chaperones. Molecular Cell, 39, 321–331.

    Article  CAS  PubMed  Google Scholar 

  • Mayer, M. P. (2013). Hsp70 chaperone dynamics and molecular mechanism. Trends in Biochemical Sciences, 38, 507–514.

    Article  CAS  PubMed  Google Scholar 

  • Mayer, M. P., & Bukau, B. (2005). Hsp70 chaperones: Cellular functions and molecular mechanism. Cellular and Molecular Life Sciences: CMLS, 62, 670–684.

    Article  CAS  PubMed  Google Scholar 

  • Mayer, M. P., & Kityk, R. (2015). Insights into the molecular mechanism of allostery in Hsp70s. Frontiers in Molecular Biosciences, 2, 58.

    Article  PubMed  PubMed Central  Google Scholar 

  • Miot, M., Reidy, M., Doyle, S. M., Hoskins, J. R., Johnston, D. M., Genest, O., Vitery, M. C., Masison, D. C., & Wickner, S. (2011). Species-specific collaboration of heat shock proteins (Hsp) 70 and 100 in thermotolerance and protein disaggregation. Proceedings of the National Academy of Sciences of the United States of America, 108, 6915–6920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mogk, A., Deuerling, E., Vorderwulbecke, S., Vierling, E., & Bukau, B. (2003a). Small heat shock proteins, ClpB and the DnaK system form a functional triade in reversing protein aggregation. Molecular Microbiology, 50, 585–595.

    Article  CAS  PubMed  Google Scholar 

  • Mogk, A., Kummer, E., & Bukau, B. (2015). Cooperation of Hsp70 and Hsp100 chaperone machines in protein disaggregation. Frontiers in Molecular Biosciences, 2, 22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mogk, A., Schlieker, C., Strub, C., Rist, W., Weibezahn, J., & Bukau, B. (2003b). Roles of individual domains and conserved motifs of the AAA+ chaperone ClpB in oligomerization, ATP hydrolysis, and chaperone activity. The Journal of Biological Chemistry, 278, 17615–17624.

    Article  CAS  PubMed  Google Scholar 

  • Mogk, A., Tomoyasu, T., Goloubinoff, P., Rudiger, S., Roder, D., Langen, H., & Bukau, B. (1999). Identification of thermolabile Escherichia coli proteins: Prevention and reversion of aggregation by DnaK and ClpB. The EMBO Journal, 18, 6934–6949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mokry, D. Z., Abrahao, J., & Ramos, C. H. (2015). Disaggregases, molecular chaperones that resolubilize protein aggregates. Anais da Academia Brasileira de Ciências, 87, 1273–1292.

    Article  CAS  PubMed  Google Scholar 

  • Muchowski, P. J., & Wacker, J. L. (2005). Modulation of neurodegeneration by molecular chaperones. Nature Reviews Neuroscience, 6, 11–22.

    Article  CAS  PubMed  Google Scholar 

  • Munro, S., & Pelham, H. R. (1987). A C-terminal signal prevents secretion of luminal ER proteins. Cell, 48, 899–907.

    Article  CAS  PubMed  Google Scholar 

  • Nillegoda, N. B., & Bukau, B. (2015). Metazoan Hsp70-based protein disaggregases: Emergence and mechanisms. Frontiers in Molecular Biosciences, 2, 57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nillegoda, N. B., Kirstein, J., Szlachcic, A., Berynskyy, M., Stank, A., Stengel, F., Arnsburg, K., Gao, X., Scior, A., Aebersold, R., Guilbride, D. L., Wade, R. C., Morimoto, R. I., Mayer, M. P., & Bukau, B. (2015). Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation. Nature, 524, 247–251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nyquist, K., & Martin, A. (2014). Marching to the beat of the ring: Polypeptide translocation by AAA+ proteases. Trends in Biochemical Sciences, 39, 53–60.

    Article  CAS  PubMed  Google Scholar 

  • Oguchi, Y., Kummer, E., Seyffer, F., Berynskyy, M., Anstett, B., Zahn, R., Wade, R. C., Mogk, A., & Bukau, B. (2012). A tightly regulated molecular toggle controls AAA+ disaggregase. Nature Structural & Molecular Biology, 19, 1338–1346.

    Article  CAS  Google Scholar 

  • Oh, H. J., Chen, X., & Subjeck, J. R. (1997). Hsp110 protects heat-denatured proteins and confers cellular thermoresistance. The Journal of Biological Chemistry, 272, 31636–31640.

    Article  CAS  PubMed  Google Scholar 

  • Oh, H. J., Easton, D., Murawski, M., Kaneko, Y., & Subjeck, J. R. (1999). The chaperoning activity of hsp110. Identification of functional domains by use of targeted deletions. The Journal of Biological Chemistry, 274, 15712–15718.

    Article  CAS  PubMed  Google Scholar 

  • Olivares, A. O., Baker, T. A., & Sauer, R. T. (2016). Mechanistic insights into bacterial AAA+ proteases and protein-remodelling machines. Nature Reviews Microbiology, 14, 33–44.

    Article  CAS  PubMed  Google Scholar 

  • Olshansky, S. J., Passaro, D. J., Hershow, R. C., Layden, J., Carnes, B. A., Brody, J., Hayflick, L., Butler, R. N., Allison, B. D., & Ludwing, D. S. (2005). A potential decline in life expectancy in the United States in the 21st century. The New England Journal of Medicine, 352, 1138–1145.

    Article  CAS  PubMed  Google Scholar 

  • Olzscha, H., Schermann, S. M., Woerner, A. C., Pinkert, S., Hecht, M. H., Tartaglia, G. G., Vendruscolo, M., Hayer-Hartl, M., Hartl, F. U., & Vabulas, R. M. (2011). Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell, 144, 67–78.

    Article  CAS  PubMed  Google Scholar 

  • Pockley, A. G., Henderson, B., & Multhoff, G. (2014). Extracellular cell stress proteins as biomarkers of human disease. Biochemical Society Transactions, 42, 1744–1751.

    Article  CAS  PubMed  Google Scholar 

  • Prahlad, V., & Morimoto, R. I. (2009). Integrating the stress response: Lessons for neurodegenerative diseases from C. elegans. Trends in Cell Biology, 19, 52–61.

    Article  CAS  PubMed  Google Scholar 

  • Przyborski, J. M., Diehl, M., & Blatch, G. L. (2015). Plasmodial HSP70s are functionally adapted to the malaria parasite life cycle. Frontiers in Molecular Biosciences, 2, 34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Qiu, X. B., Shao, Y. M., Miao, S., & Wang, L. (2006). The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones. Cellular and Molecular Life Sciences: CMLS, 63, 2560–2570.

    Article  CAS  PubMed  Google Scholar 

  • Quinlan, R. A., Brenner, M., Goldman, J. E., & Messing, A. (2007). GFAP and its role in Alexander disease. Experimental Cell Research, 313, 2077–2087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Radons, J. (2016). The human HSP70 family of chaperones: Where do we stand? Cell Stress & Chaperones, 21, 379–404.

    Article  CAS  Google Scholar 

  • Ramos, C. H., & Ferreira, S. T. (2005). Protein folding, misfolding and aggregation: Evolving concepts and conformational diseases. Protein and Peptide Letters, 12, 213–222.

    Article  CAS  PubMed  Google Scholar 

  • Rampelt, H., Kirstein-Miles, J., Nillegoda, N. B., Chi, K., Scholz, S. R., Morimoto, R. I., & Bukau, B. (2012). Metazoan Hsp70 machines use Hsp110 to power protein disaggregation. The EMBO Journal, 31, 4221–4235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raviol, H., Bukau, B., & Mayer, M. P. (2006a). Human and yeast Hsp110 chaperones exhibit functional differences. FEBS Letters, 580, 168–174.

    Article  CAS  PubMed  Google Scholar 

  • Raviol, H., Sadlish, H., Rodriguez, F., Mayer, M. P., & Bukau, B. (2006b). Chaperone network in the yeast cytosol: Hsp110 is revealed as an Hsp70 nucleotide exchange factor. The EMBO Journal, 25, 2510–2518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rinaldi, C., & Fischbeck, K. H. (2015). Pathological mechanisms of Polyglutamine diseases. Nature Education, 8, 5.

    Google Scholar 

  • Rosenzweig, R., Moradi, S., Zarrine-Afsar, A., Glover, J. R., & Kay, L. E. (2013). Unraveling the mechanism of protein disaggregation through a ClpB-DnaK interaction. Science (New York, N.Y.), 339, 1080–1083.

    Article  CAS  Google Scholar 

  • Sarbeng, E. B., Liu, Q., Tian, X., Yang, J., Li, H., Wong, J. L., Zhou, L., & Liu, Q. (2015). A functional DnaK dimer is essential for the efficient interaction with Hsp40 heat shock protein. The Journal of Biological Chemistry, 290, 8849–8862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Satyal, S. H., Schmidt, E., Kitagawa, K., Sondheimer, N., Lindquist, S., Kramer, J. M., & Morimoto, R. I. (2000). Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America, 97, 5750–5755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schirmer, E. C., Glover, J. R., Singer, M. A., & Lindquist, S. (1996). HSP100/Clp proteins: A common mechanism explains diverse functions. Trends in Biochemical Sciences, 21, 289–296.

    Article  CAS  PubMed  Google Scholar 

  • Schlee, S., Beinker, P., Akhrymuk, A., & Reinstein, J. (2004). A chaperone network for the resolubilization of protein aggregates: Direct interaction of ClpB and DnaK. Journal of Molecular Biology, 336, 275–285.

    Article  CAS  PubMed  Google Scholar 

  • Schlieker, C., Tews, I., Bukau, B., & Mogk, A. (2004). Solubilization of aggregated proteins by ClpB/DnaK relies on the continuous extraction of unfolded polypeptides. FEBS Letters, 578, 351–356.

    Article  CAS  PubMed  Google Scholar 

  • Schuermann, J. P., Jiang, J., Cuellar, J., Llorca, O., Wang, L., Gimenez, L. E., Jin, S., Taylor, A. B., Demeler, B., Morano, K. A., Hart, P. J., Valpuesta, J. M., Lafer, E. M., & Sousa, R. (2008). Structure of the Hsp110: Hsc70 nucleotide exchange machine. Molecular Cell, 31, 232–243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shorter, J. (2011). The mammalian disaggregase machinery: Hsp110 synergizes with Hsp70 and Hsp40 to catalyze protein disaggregation and reactivation in a cell-free system. PLoS One, 6, e26319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shorter, J. (2017). Designer protein disaggregases to counter neurodegenerative disease. Current Opinion in Genetics & Development, 44, 1–8.

    Article  CAS  Google Scholar 

  • Shorter, J., & Lindquist, S. (2004). Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers. Science (New York, NY), 304, 1793–1797.

    Article  CAS  Google Scholar 

  • Shorter, J., & Lindquist, S. (2006). Destruction or potentiation of different prions catalyzed by similar Hsp104 remodeling activities. Molecular Cell, 23, 425–438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shorter, J., & Lindquist, S. (2008). Hsp104, Hsp70 and Hsp40 interplay regulates formation, growth and elimination of Sup35 prions. The EMBO Journal, 27, 2712–2724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shrestha, L., & Young, J. (2016). Function and Chemotypes of human Hsp70 chaperones. Current Topics in Medicinal Chemistry, 16, 2812–2828.

    Article  CAS  PubMed  Google Scholar 

  • Sielaff, B., & Tsai, F. T. (2010). The M-domain controls Hsp104 protein remodeling activity in an Hsp70/Hsp40-dependent manner. Journal of Molecular Biology, 402, 30–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silva, J. L., De Moura Gallo, C. V., Costa, D. C., & Rangel, L. P. (2014). Prion-like aggregation of mutant p53 in cancer. Trends in Biochemical Sciences, 39, 260–267.

    Article  CAS  PubMed  Google Scholar 

  • Silverman, G. A., Pak, S. C., & Perlmutter, D. H. (2013). Disorders of protein misfolding: Alpha-1-antitrypsin deficiency as prototype. The Journal of Pediatrics, 163, 320–326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Snider, J., & Houry, W. A. (2008). AAA+ proteins: Diversity in function, similarity in structure. Biochemical Society Transactions, 36, 72–77.

    Article  CAS  PubMed  Google Scholar 

  • Sousa, R. (2014). Structural mechanisms of chaperone mediated protein disaggregation. Frontiers in Molecular Biosciences, 1, 12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Srivastava, P. K. (2005). Immunotherapy for human cancer using heat shock protein-peptide complexes. Current Oncology Reports, 7, 104–108.

    Article  CAS  PubMed  Google Scholar 

  • Stewart, K. L., & Radford, S. E. (2017). Amyloid plaques beyond αβ: A survey of the diverse modulators of amyloid aggregation. Biophysical Reviews, 4, 405–419.

    Article  CAS  Google Scholar 

  • Summers, D. W., Douglas, P. M., Ramos, C. H., & Cyr, D. M. (2009). Polypeptide transfer from Hsp40 to Hsp70 molecular chaperones. Trends in Biochemical Sciences, 34, 230–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sweeny, E. A., & Shorter, J. (2016). Mechanistic and structural insights into the Prion-Disaggregase activity of Hsp104. Journal of Molecular Biology, 428, 1870–1885.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi, T., Katada, S., & Onodera, O. (2010). Polyglutamine diseases: Where does toxicity come from? What is toxicity? Where are we going? Journal of Molecular Cell Biology, 2, 180–191.

    Article  CAS  PubMed  Google Scholar 

  • Tamarappoo, B. K., Yang, B., & Verkman, A. S. (1999). Misfolding of mutant aquaporin-2 water channels in nephrogenic diabetes insipidus. The Journal of Biological Chemistry, 274, 34825–34831.

    Article  CAS  PubMed  Google Scholar 

  • Tiroli-Cepeda, A. O., & Ramos, C. H. (2011). An overview of the role of molecular chaperones in protein homeostasis. Protein and Peptide Letters, 18, 101–109.

    Article  CAS  PubMed  Google Scholar 

  • Torrente, M. P., & Shorter, J. (2013). The metazoan protein disaggregase and amyloid depolymerase system: Hsp110, Hsp70, Hsp40, and small heat shock proteins. Prion, 7, 457–463.

    Article  CAS  PubMed  Google Scholar 

  • Tytell, M. (2005). Release of heat shock proteins (Hsps) and the effects of extracellular Hsps on neural cells and tissues. International Journal of Hyperthermia: the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group, 21, 445–455.

    Article  CAS  Google Scholar 

  • Valastyan, J. S., & Lindquist, S. (2014). Mechanisms of protein-folding diseases at a glance. Disease Models & Mechanisms, 7, 9–14.

    Article  CAS  Google Scholar 

  • Vashist, S., Cushman, M., & Shorter, J. (2010). Applying Hsp104 to protein-misfolding disorders. Biochemistry and Cell Biology = Biochimie et biologie cellulaire, 88, 1–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vicente Miranda, H., & Outeiro, T. F. (2010). The sour side of neurodegenerative disorders: The effects of protein glycation. The Journal of Pathology, 221, 13–25.

    Article  PubMed  CAS  Google Scholar 

  • Wallace, E. W., Kear-Scott, J. L., Pilipenko, E. V., Schwartz, M. H., Laskowski, P. R., Rojek, A. E., Katanski, C. D., Riback, J. A., Dion, M. F., Franks, A. M., Airoldi, E. M., Pan, T., Budnik, B. A., & Drummond, D. A. (2015). Reversible, specific, active aggregates of endogenous proteins assemble upon heat stress. Cell, 162, 1286–1298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walsh, P., Bursac, D., Law, Y. C., Cyr, D., & Lithgow, T. (2004). The J-protein family: Modulating protein assembly, disassembly and translocation. EMBO Reports, 5, 567–571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warrick, J. M., Chan, H. Y., Gray-Board, G. L., Chai, Y., Paulson, H. L., & Bonini, N. M. (1999). Suppression of polyglutamine-mediated neurodegeneration in drosophila by the molecular chaperone HSP70. Nature Genetics, 23, 425–428.

    Article  CAS  PubMed  Google Scholar 

  • Weibezahn, J., Tessarz, P., Schlieker, C., Zahn, R., Maglica, Z., Lee, S., Zentgraf, H., Weber-Ban, E. U., Dougan, D. A., Tsai, F. T., Mogk, A., & Bukau, B. (2004). Thermotolerance requires refolding of aggregated proteins by substrate translocation through the central pore of ClpB. Cell, 119, 653–665.

    Article  CAS  PubMed  Google Scholar 

  • Winkler, J., Tyedmers, J., Bukau, B., & Mogk, A. (2012). Chaperone networks in protein disaggregation and prion propagation. Journal of Structural Biology, 179, 152–160.

    Article  CAS  PubMed  Google Scholar 

  • Wolfe, K. J., & Cyr, D. M. (2011). Amyloid in neurodegenerative diseases: Friend or foe? Seminars in Cell & Developmental Biology, 22, 476–481.

    Article  CAS  Google Scholar 

  • Yedidi, R. S., Wendler, P., & Enenkel, C. (2017). AAA-ATPases in protein degradation. Frontiers in Molecular Biosciences, 4, 42.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yokom, A. L., Gates, S. N., Jackrel, M. E., Mack, K. L., Su, M., Shorter, J., & Southworth, D. R. (2016). Spiral architecture of the Hsp104 disaggregase reveals the basis for polypeptide translocation. Nature Structural & Molecular Biology, 23, 830–837.

    Article  CAS  Google Scholar 

  • Young, J. C. (2010). Mechanisms of the Hsp70 chaperone system. Biochemistry and Cell Biology = Biochimie et biologie cellulaire, 88, 291–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young, J. C. (2014). The role of the cytosolic HSP70 chaperone system in diseases caused by misfolding and aberrant trafficking of ion channels. Disease Models & Mechanisms, 7, 319–329.

    Article  CAS  Google Scholar 

  • Zietkiewicz, S., Krzewska, J., & Liberek, K. (2004). Successive and synergistic action of the Hsp70 and Hsp100 chaperones in protein disaggregation. The Journal of Biological Chemistry, 279, 44376–44383.

    Article  CAS  PubMed  Google Scholar 

  • Zietkiewicz, S., Lewandowska, A., Stocki, P., & Liberek, K. (2006). Hsp70 chaperone machine remodels protein aggregates at the initial step of Hsp70-Hsp100-dependent disaggregation. The Journal of Biological Chemistry, 281, 7022–7029.

    Article  CAS  PubMed  Google Scholar 

  • Zolkiewski, M. (2006). A camel passes through the eye of a needle: Protein unfolding activity of Clp ATPases. Molecular Microbiology, 61, 1094–1100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zolkiewski, M., Zhang, T., & Nagy, M. (2012). Aggregate reactivation mediated by the Hsp100 chaperones. Archives of Biochemistry and Biophysics, 520, 1–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zuiderweg, E. R., Hightower, L. E., & Gestwicki, J. E. (2017). The remarkable multivalency of the Hsp70 chaperones. Cell Stress & Chaperones, 22, 173–189.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

FAPESP (2012/50161-8), CNPq and CAPES for grants and fellowships.

Author information

Authors and Affiliations

  1. Department of Organic Chemistry, Institute of Chemistry, University of Campinas – UNICAMP, Campinas, SP, Brazil

    Maria Luiza Caldas Nogueira, Juliana Crotti Franco, Gabriela de Mello Gandelini & Carlos Henrique Inacio Ramos

Authors
  1. Maria Luiza Caldas Nogueira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juliana Crotti Franco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gabriela de Mello Gandelini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carlos Henrique Inacio Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlos Henrique Inacio Ramos .

Editor information

Editors and Affiliations

  1. Department of Medicine and Precision Therapeutics Proteogenomics Diagnostic Center, Eleanor N. Dana Cancer Center, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA

    Alexzander A A Asea

  2. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Punit Kaur

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Nogueira, M.L.C., Franco, J.C., de Mello Gandelini, G., Ramos, C.H.I. (2018). The 70 KDA Heat Shock Protein Hsp70 as Part of a Protein Disaggregase System. In: Asea, A., Kaur, P. (eds) Regulation of Heat Shock Protein Responses. Heat Shock Proteins, vol 13. Springer, Cham. https://doi.org/10.1007/978-3-319-74715-6_7

Download citation

Publish with us

Policies and ethics

Search

Navigation