Hsp110 Chaperones

Abstract

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 Figurec. 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., ).
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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.

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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.

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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.

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