Hsp110 Chaperones


Hsp70s are a diverse family of chaperones that execute a variety of proteostatic and protein processing reactions. They include the eukaryotic Hsp110s, which function as nucleotide exchange factors for other Hsp70s and thereby regulate association of Hsp70s with their protein substrates. Hsp110s also display protein substrateā€binding domains that shield misfolded proteins from aggregation. Through these activities, Hsp110s contribute to a range of protein processing reactions including recovery from stresses such as heat or ischemic shocks, protein aggregation inhibition and aggregate solubilisation, prion propagation and assembly/disassembly of polymeric protein complexes. These functions result in Hsp110s, contributing both positively and negatively to multiple disease etiologies. Positively, because they inhibit degenerative diseases associated with protein aggregation and negatively because these same activities stimulate cancer proliferation and allow cancer cells to survive the stress of radiologic and chemotherapies. Consequently, Hsp110s are targets of therapeutic approaches that aim to both stimulate and inhibit their activities.

Key Concepts

  • Hsp70s are proteins that bind other, often misfolded, proteins so as to either inhibit interactions made by those proteins, break up protein:protein associations or move proteins between cellular compartments.
  • ATP binding causes Hsp70s to release their bound protein substrates, while ADP causes them to hold tightly to those substrates.
  • Hsp110s cause Hsp70s to release ADP so that they can then bind ATP, which then causes the Hsp70 to release its bound protein substrate. In this way, Hsp110s regulate Hsp70:substrate associations.
  • The crystal structure of an Hsp110:Hsp70 complex reveals how Hsp110 induces nucleotide exchange and why it is so effective at doing so.
  • Hsp110s are also able to bind directly to misfolded proteins to block their aggregation, but cannot unfold and refold these proteins as canonical Hsp70s can.
  • Hsp110s strongly stimulate the ability of canonical Hsp70s to solubilise protein aggregates in vitro.
  • Hsp110s are induced by stresses such as heat or ischaemic shocks and assist cellular recovery from such traumas.
  • Hsp110s inhibit protein aggregation and help solubilise protein aggregates in vivo.
  • Hsp110 roles in aggregate solubilisation and aggregation inhibition makes stimulation of their activities a goal for treatment of degenerative diseases associated with protein aggregation.
  • Hsp110 activities support cancer cell growth and therapeutic resistance and make Hsp110 inhibition a goal in cancer treatment.

Keywords: Hsp70; Hsp110; chaperone; protein aggregation; nucleotide exchange factor; heat shock; ischaemia; neurodegenerative disease

Figure 1. The conformational states of canonical Hsp70s and Hsp110. (a) Representative conformation of Escherichia coli Hsp70 (DnaK) in its substrate bound and nucleotide‐free state [pdb 2KHO (Bertelsen et al., ); with the substrate molecule in dark grey imported from 1DKX (Zhu et al., )]. In this state, the NBD (nucleotide‐binding domain) (in light grey) is in a relatively open conformation, the interdomain linker (green) is solvent exposed, and the SBD (substrate‐binding domain) (with the β‐sandwich portion in orange and the helical lid in cyan) is tightly closed around the substrate. (b) DnaK in its substrate free and ATP (adenosine triphosphate) bound state [pdb 4B9Q (Kityk et al., )]. ATP binding induces rotation of NBD subdomains IA and IB towards IIB resulting in closure of the NBD and widening of the groove between subdomains IA and IIA which allows the interdomain linker to bind in this groove, followed by binding of SBDβ to this surface. The interactions with the NBD induce the changes shown in the expanded view of SBDβ (orange: closed, apo/ADP (adenosine diphosphate) state; cyan: open, ATP state), which open the 'latch' loops so as to disrupt the interaction with the helical lid (which then binds to NBD subdomain IB) and release the bound substrate. (c) Structure of yeast Hsp110 [Sse1p; pdb 2QXL (Liu and Hendrickson, )] bound to ATP shows a conformation like DnaK*ATP (panel b).
Figure 2. Mechanisms of Hsp110‐mediated nucleotide exchange. (a) Ribbon model of Hsp110 (Sse1p) with ADP*BeFx in its active site (space‐filling representation in red) in complex with Hsc70 with bound ADP [also in red; pdb 3C7N (Schuermann et al., )]. Hsp110 domains are coloured as in Figure c. Superimposed on the open (tan coloured) Hsc70 ribbon is a model (light blue) of the closed NBD conformation as seen in Hsp110‐free ATP‐bound Hsp70 [pdb 4B9Q (Kityk et al., )]. Positively charged amino acid side chains lining the side of Hsc70 facing Hsp110 SBDα are in blue ball‐and‐stick representation and are opposed by red negatively charged side chains on the Hsp110 helices facing the Hsc70. These interactions pull on Hsc70 subdomains IA and IB to open the NBD as shown so as to facilitate ADP release. (b) Ribbon model of just the Hsp110 (grey) and Hsc70 (tan) NBDs and nucleotides (red) from panel (a). Also shown in space‐filling representation are Hsp110 S32 and Hsc70 Q33, which make symmetric bridging interactions to the adenine N7 of the nucleotides bound within the active sites of the partner protein in the complex.
Figure 3. Hsp110 domain organisation in the Sse1p:Hsp70 complex and in the Hsp110/Grp170 family. (a) Ribbon model of the yeast Hsp110(Sse1p):Hsp70 complex [3C7N (Schuermann et al., )] with the NBD, SBDβ, insertion loop and SBDα elements of the Hsp110 coloured, respectively: red orange, orange, red and yellow. The Hsp70 NBD, SBDβ and SBDα are coloured, respectively: cyan, green and blue. The blue and yellow circles highlight the positions of the substrate‐binding sites in, respectively, Hsp110 and Hsp70. (b) Lengths and domain organisation of mouse Hsp70, yeast Hsp110 (Sse1p), mouse Hsp110 and the ER (endoplasmic reticulum)‐localised mouse Hsp110 homologue Grp170. The colouring of the domains and structural elements corresponds to the colouring used in panel (a). The organisation and lengths of the domains in yeast Hsp110, mouse Hsp110 and mouse Grp170 correspond closely to those in mouse Hsp70. However, the Hsp110s are extended by insertion of loops of varying sizes near the C‐terminus of the SBDβ, as well as by the presence of longer tails (coloured grey) at the C‐terminus of SBDα, which, based on their highly polar/charged amino acid composition, are predicted to be largely unstructured.
Figure 4. Alternate splicing and phosphorylation of the Hsp110 insertion loops. (a) Human Hsp110a modelled on yeast Hsp110 (Sse1p) from the Sse1p:Hsp70 structure (Schuermann et al., ) with its NBD, SBDβ, insertion loop and SBDα in blue, cyan, magenta and orange, respectively. Also shown in red, space‐filling representation are the side chains for S509 and S510 whose phosphorylation in vivo and in vitro (by casein kinase II) appears to modulate Hsp110 activity (Ishihara et al., , ). (b) Model for human Hsp110β which differs from Hsp110α in being alternatively spliced [missing residues 529–572 (Ishihara et al., , , )] and being nuclear, rather than cytoplasmically, localised (Saito et al., ).


Abrams JL, Verghese J, Gibney PA and Morano KA (2014) Hierarchical functional specificity of cytosolic heat shock protein 70 (Hsp70) nucleotide exchange factors in yeast. Journal of Biological Chemistry 289: 13155–13167.

Andreasson C, Fiaux J, Rampelt H, Mayer MP and Bukau B (2008) Hsp110 is a nucleotide‐activated exchange factor for Hsp70. Journal of Biological Chemistry 283 (14): 8877–8884.

Andreasson C, Rampelt H, Fiaux J, Druffel‐Augustin S and Bukau B (2010) The endoplasmic reticulum Grp170 acts as a nucleotide exchange factor of Hsp70 via a mechanism similar to that of the cytosolic Hsp110. Journal of Biological Chemistry 285: 12445–12453.

Behnke J and Hendershot LM (2014) The large Hsp70 Grp170 binds to unfolded protein substrates in vivo with a regulation distinct from conventional Hsp70s. Journal of Biological Chemistry 289: 2899–2907.

Ben‐Zvi A, De Los Rios P, Dietler G and Goloubinoff P (2004) Active solubilization and refolding of stable protein aggregates by cooperative unfolding action of individual hsp70 chaperones. Journal of Biological Chemistry 279: 37298–37303.

Bertelsen EB, Chang L, Gestwicki JE and Zuiderweg ER (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.

Bracher A and Verghese J (2015a) GrpE, Hsp110/Grp170, HspBP1/Sil1 and BAG domain proteins: nucleotide exchange factors for Hsp70 molecular chaperones. Sub‐cellular Biochemistry 78: 1–33.

Bracher A and Verghese J (2015b) The nucleotide exchange factors of Hsp70 molecular chaperones. Frontiers in Molecular Biosciences 2: 10.

Brehmer D, Rudiger S, Gassler CS, et al. (2001) Tuning of chaperone activity of Hsp70 proteins by modulation of nucleotide exchange. Nature Structural Biology 8: 427–432.

Dai C, Whitesell L, Rogers AB and Lindquist S (2007) Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130: 1005–1018.

DiDomenico BJ, Bugaisky GE and Lindquist S (1982) Heat shock and recovery are mediated by different translational mechanisms. Proceedings of the National Academy of Sciences of the United States of America 79: 6181–6185.

Dorard C, de Thonel A, Collura A, et al. (2011) Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis. Nature Medicine 17: 1283–1289.

Dragovic Z, Broadley SA, Shomura Y, Bracher A and Hartl FU (2006) Molecular chaperones of the Hsp110 family act as nucleotide exchange factors of Hsp70s. EMBO Journal 25: 2519–2528.

Easton DP, Kaneko Y and Subjeck JR (2000) The hsp110 and Grp1 70 stress proteins: newly recognized relatives of the Hsp70s. Cell Stress & Chaperones 5: 276–290.

Eisenberg D, Nelson R, Sawaya MR, et al. (2006) The structural biology of protein aggregation diseases: fundamental questions and some answers. Accounts of Chemical Research 39: 568–575.

Eroglu B, Moskophidis D and Mivechi NF (2010) Loss of Hsp110 leads to age‐dependent tau hyperphosphorylation and early accumulation of insoluble amyloid beta. Molecular and Cellular Biology 30: 4626–4643.

Eroglu B, Kimbler DE, Pang J, et al. (2014) Therapeutic Inducers of the HSP70/HSP110 Protect Mice Against Traumatic Brain Injury. Journal of Neurochemistry 130 (5): 626–641.

Finka A, Sharma SK and Goloubinoff P (2015) Multi‐layered molecular mechanisms of polypeptide holding, unfolding and disaggregation by HSP70/HSP110 chaperones. Frontiers in Molecular Biosciences 2: 29.

Flaherty KM, Wilbanks SM, DeLuca‐Flaherty C and McKay DB (1994) Structural basis of the 70‐kilodalton heat shock cognate protein ATP hydrolytic activity. II. Structure of the active site with ADP or ATP bound to wild type and mutant ATPase fragment. Journal of Biological Chemistry 269: 12899–12907.

Gamer J, Bujard H and Bukau B (1992) Physical interaction between heat shock proteins DnaK, DnaJ, and GrpE and the bacterial heat shock transcription factor sigma 32. Cell 69: 833–842.

Gao B, Emoto Y, Greene L and Eisenberg E (1993) Nucleotide binding properties of bovine brain uncoating ATPase. Journal of Biological Chemistry 268: 8507–8513.

Gao X, Carroni M, Nussbaum‐Krammer C, et al. (2015) Human Hsp70 disaggregase reverses Parkinson's‐linked alpha‐synuclein amyloid fibrils. Molecular Cell 59: 781–793.

Gotoh K, Nonoguchi K, Higashitsuji H, et al. (2004) Apg‐2 has a chaperone‐like activity similar to Hsp110 and is overexpressed in hepatocellular carcinomas. FEBS Letters 560: 19–24.

Hartl FU and Hayer‐Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295: 1852–1858.

Haslbeck M, Franzmann T, Weinfurtner D and Buchner J (2005) Some like it hot: the structure and function of small heat‐shock proteins. Nature Structural & Molecular Biology 12: 842–846.

Hohfeld J and Hartl FU (1994) Post‐translational protein import and folding. Current Opinion in Cell Biology 6: 499–509.

Hosaka S, Nakatsura T, Tsukamoto H, et al. (2006) Synthetic small interfering RNA targeting heat shock protein 105 induces apoptosis of various cancer cells both in vitro and in vivo. Cancer Science 97: 623–632.

Ishihara K, Yasuda K and Hatayama T (1999) Molecular cloning, expression and localization of human 105 kDa heat shock protein, hsp105. Biochimica et Biophysica Acta 1444: 138–142.

Ishihara K, Yasuda K and Hatayama T (2000) Phosphorylation of the 105‐kDa heat shock proteins, HSP105alpha and HSP105beta, by casein kinase II. Biochemical and Biophysical Research Communications 270: 927–931.

Ishihara K, Yamagishi N and Hatayama T (2003) Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. Biochemical Journal 371: 917–925.

Jiang J, Prasad K, Lafer EM and Sousa R (2005) Structural basis of interdomain communication in the Hsc70 chaperone. Molecular Cell 20: 513–524.

Kai M, Nakatsura T, Egami H, et al. (2003) Heat shock protein 105 is overexpressed in a variety of human tumors. Oncology Reports 10: 1777–1782.

Kaneko Y, Kimura T, Kishishita M, Noda Y and Fujita J (1997a) Cloning of apg‐2 encoding a novel member of heat shock protein 110 family. Gene 189: 19–24.

Kaneko Y, Kimura T, Nishiyama H, Noda Y and Fujita J (1997b) Developmentally regulated expression of APG‐1, a member of heat shock protein 110 family in murine male germ cells. Biochemical and Biophysical Research Communications 233: 113–116.

Kaneko Y, Nishiyama H, Nonoguchi K, et al. (1997c) A novel hsp110‐related gene, apg‐1, that is abundantly expressed in the testis responds to a low temperature heat shock rather than the traditional elevated temperatures. Journal of Biological Chemistry 272: 2640–2645.

Kim H, Huh PW, Kim CM, et al. (2001a) Cerebral activation and distribution of inducible hsp110 and hsp70 mRNAs following focal ischemia in rat. Toxicology 167: 135–144.

Kim SW, Yoo IS, Koh HS and Kwon OY (2001b) Ischemia‐responsive protein (irp94) is up‐regulated by endoplasmic reticulum stress. Zeitschrift für Naturforschung. Section C 56: 1169–1171.

Kityk R, Kopp J, Sinning I and Mayer MP (2012) Structure and dynamics of the ATP‐bound open conformation of Hsp70 chaperones. Molecular Cell 48 (6): 863–874.

Kuo Y, Ren S, Lao U, Edgar BA and Wang T (2013) Suppression of polyglutamine protein toxicity by co‐expression of a heat‐shock protein 40 and a heat‐shock protein 110. Cell Death & Disease 4: e833.

Li Y, Chen X, Shi M, et al. (2013) Proteomic‐based identification of Apg‐2 as a therapeutic target for chronic myeloid leukemia. Cellular Signalling 25: 2604–2612.

Liu Q and Hendrickson WA (2007) Insights into hsp70 chaperone activity from a crystal structure of the yeast hsp110 sse1. Cell 131: 106–120.

Makhnevych T and Houry WA (2013) The control of spindle length by Hsp70 and Hsp110 molecular chaperones. FEBS Letters 587: 1067–1072.

Matlack KE, Misselwitz B, Plath K and Rapoport TA (1999) BiP acts as a molecular ratchet during posttranslational transport of prepro‐alpha factor across the ER membrane. Cell 97: 553–564.

Mattoo RU, Sharma SK, Priya S, Finka A and 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. Journal of Biological Chemistry 288: 21399–21411.

Morgan JR, Jiang JW, Oliphint PA, et al. (2013) A role for an Hsp70 nucleotide exchange factor in the regulation of synaptic vesicle endocytosis. Journal of Neuroscience 33: 8009–8021.

Muchowski PJ and Wacker JL (2005) Modulation of neurodegeneration by molecular chaperones. Nature Reviews. Neuroscience 6: 11–22.

Nillegoda NB and Bukau B (2015) Metazoan Hsp70‐based protein disaggregases: emergence and mechanisms. Frontiers in Molecular Biosciences 2: 57.

Nillegoda NB, Kirstein J, Szlachcic A, et al. (2015) Crucial HSP70 co‐chaperone complex unlocks metazoan protein disaggregation. Nature 524: 247–251.

Oh HJ, Chen X and Subjeck JR (1997) Hsp110 protects heat‐denatured proteins and confers cellular thermoresistance. Journal of Biological Chemistry 272: 31636–31640.

Oh HJ, Easton D, Murawski M, Kaneko Y and Subjeck JR (1999) The chaperoning activity of hsp110. Identification of functional domains by use of targeted deletions. Journal of Biological Chemistry 274: 15712–15718.

Pollanen MS, Bergeron C and Weyer L (1993) Deposition of detergent‐resistant neurofilaments into Lewy body fibrils. Brain Research 603: 121–124.

Rampelt H, Kirstein‐Miles J, Nillegoda NB, et al. (2012) Metazoan Hsp70 machines use Hsp110 to power protein disaggregation. EMBO Journal 31: 4221–4235.

Rauch JN and Gestwicki JE (2014) Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally distinct complexes in vitro. Journal of Biological Chemistry 289: 1402–1414.

Rerole AL, Jego G and Garrido C (2011) Hsp70: anti‐apoptotic and tumorigenic protein. Methods in Molecular Biology (Clifton, NJ) 787: 205–230.

Richter K, Haslbeck M and Buchner J (2010) The heat shock response: life on the verge of death. Molecular Cell 40: 253–266.

Ross CA and Poirier MA (2005) Opinion: what is the role of protein aggregation in neurodegeneration? Nature Reviews. Molecular Cell Biology 6: 891–898.

Sadlish H, Rampelt H, Shorter J, et al. (2008) Hsp110 chaperones regulate prion formation and propagation in S. cerevisiae by two discrete activities. PLoS One 3: e1763.

Saito Y, Yamagishi N and Hatayama T (2009) Nuclear localization mechanism of Hsp105beta and its possible function in mammalian cells. Journal of Biochemistry 145: 185–191.

Saxena A, Banasavadi‐Siddegowda YK, Fan Y, et al. (2012) Human heat shock protein 105/110 kDa (Hsp105/110) regulates biogenesis and quality control of misfolded cystic fibrosis transmembrane conductance regulator at multiple levels. Journal of Biological Chemistry 287: 19158–19170.

Schuermann JP, Jiang J, Cuellar J, et al. (2008) Structure of the Hsp110:Hsc70 nucleotide exchange machine. Molecular Cell 31: 232–243.

Shaner L, Sousa R and Morano KA (2006) Characterization of Hsp70 binding and nucleotide exchange by the yeast Hsp110 chaperone Sse1. Biochemistry 45: 15075–15084.

Shaner L, Gibney PA and Morano KA (2008) The Hsp110 protein chaperone Sse1 is required for yeast cell wall integrity and morphogenesis. Current Genetics 54: 1–11.

Shomura Y, Dragovic Z, Chang HC, et al. (2005) Regulation of Hsp70 function by HspBP1: structural analysis reveals an alternate mechanism for Hsp70 nucleotide exchange. Molecular Cell 17: 367–379.

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.

Sousa RJ (2014) Structural mechanisms of chaperone mediated protein disaggregation. Frontiers in Molecular Biosciences 1: 12.

Tsapara A, Matter K and Balda MS (2006) The heat‐shock protein Apg‐2 binds to the tight junction protein ZO‐1 and regulates transcriptional activity of ZONAB. Molecular Biology of the Cell 17: 1322–1330.

Voisine C, Craig EA, Zufall N, et al. (1999) The protein import motor of mitochondria: unfolding and trapping of preproteins are distinct and separable functions of matrix Hsp70. Cell 97: 565–574.

Wakatsuki T and Hatayama T (1998) Characteristic expression of 105‐kDa heat shock protein (HSP105) in various tissues of nonstressed and heat‐stressed rats. Biological & Pharmaceutical Bulletin 21: 905–910.

Xu X, Sarbeng EB, Vorvis C, et al. (2012) Unique peptide substrate binding properties of 110‐kDa heat‐shock protein (Hsp110) determine its distinct chaperone activity. Journal of Biological Chemistry 287: 5661–5672.

Yam AY, Albanese V, Lin HT and Frydman J (2005) Hsp110 cooperates with different cytosolic HSP70 systems in a pathway for de novo folding. The Journal of Biological Chemistry 280: 41252–41261.

Yamashita H, Kawamata J, Okawa K, et al. (2007) Heat‐shock protein 105 interacts with and suppresses aggregation of mutant Cu/Zn superoxide dismutase: clues to a possible strategy for treating ALS. Journal of Neurochemistry 102: 1497–1505.

Zhu X, Zhao X, Burkholder WF, et al. (1996) Structural analysis of substrate binding by the molecular chaperone DnaK. Science 272: 1606–1614.

Further Reading

Barral JM, Broadley SA, Schaffar G and Hartl FU (2004) Roles of molecular chaperones in protein misfolding diseases. Seminars in Cell & Developmental Biology 15: 17–29.

Brehmer D, Rudiger S, Gassler CS, et al. (2001) Tuning of chaperone activity of Hsp70 proteins by modulation of nucleotide exchange. Nature Structural Biology 8 (5): 427–432.

Bukau B, Weissman J and Horwich A (2006) Molecular chaperones and protein quality control. Cell 125: 443–451.

Finka A, Mattoo RU and Goloubinoff P (2016) Experimental milestones in the discovery of molecular chaperones as polypeptide unfolding enzymes. Annual Review of Biochemistry 85: 715–742.

Hinault MP, Farina‐Henriquez‐Cuendet A and Goloubinoff P (2011) Molecular chaperones and associated cellular clearance mechanisms against toxic protein conformers in Parkinson's disease. Neuro‐Degenerative Diseases 8: 397–412.

Kityk R, Vogel M, Schlecht R, Bukau B and Mayer MP (2015) Pathways of allosteric regulation in Hsp70 chaperones. Nature Communications 6: 8308.

Mattoo RU and Goloubinoff P (2014) Molecular chaperones are nanomachines that catalytically unfold misfolded and alternatively folded proteins. Cellular and Molecular Life Sciences: CMLS 71 (17): 3311–3325.

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

Young JC, Barral JM and Ulrich Hartl F (2003) More than folding: localized functions of cytosolic chaperones. Trends in Biochemical Sciences 28: 541–547.

Young JC, Agashe VR, Siegers K and Hartl FU (2004) Pathways of chaperone‐mediated protein folding in the cytosol. Nature Reviews. Molecular Cell Biology 5: 781–791.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Sousa, Rui(Dec 2016) Hsp110 Chaperones. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027011]