HSP104/YLL026W Summary Help

Standard Name HSP104 1
Systematic Name YLL026W
Feature Type ORF, Verified
Description Disaggregase; heat shock protein that cooperates with Ydj1p (Hsp40) and Ssa1p (Hsp70) to refold and reactivate previously denatured, aggregated proteins; responsive to stresses including: heat, ethanol, and sodium arsenite; involved in [PSI+] propagation; protein becomes more abundant and forms cytoplasmic foci in response to DNA replication stress; potentiated Hsp104p variants decrease TDP-43 proteotoxicity by eliminating its cytoplasmic aggregation (2, 3, 4, 5, 6, 7, 8, 9 and see Summary Paragraph)
Name Description Heat Shock Protein 6
Chromosomal Location
ChrXII:88623 to 91349 | ORF Map | GBrowse
Gene Ontology Annotations All HSP104 GO evidence and references
  View Computational GO annotations for HSP104
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Regulators 31 genes
Classical genetics
dominant negative
Large-scale survey
148 total interaction(s) for 99 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 57
  • Affinity Capture-RNA: 5
  • Affinity Capture-Western: 9
  • Biochemical Activity: 1
  • Co-crystal Structure: 4
  • Co-localization: 4
  • FRET: 1
  • Protein-peptide: 3
  • Reconstituted Complex: 16
  • Two-hybrid: 1

Genetic Interactions
  • Dosage Rescue: 9
  • Negative Genetic: 7
  • Phenotypic Enhancement: 4
  • Phenotypic Suppression: 16
  • Positive Genetic: 2
  • Synthetic Growth Defect: 3
  • Synthetic Lethality: 1
  • Synthetic Rescue: 5

Expression Summary
Length (a.a.) 908
Molecular Weight (Da) 102,034
Isoelectric Point (pI) 5.2
Phosphorylation PhosphoGRID | PhosphoPep Database
sequence information
ChrXII:88623 to 91349 | ORF Map | GBrowse
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Most Recent Updates
Coordinates Sequence
CDS 1..2727 88623..91349 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
External Links All Associated Seq | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000003949

HSP104 encodes a general anti-stress chaperone of the HSP100 gene family (reviewed in 10). Unlike most chaperones that prevent proteins from aggregating, Hsp104p, in conjunction with the chaperone and co-chaperone Ssa1p and Ydj1p, helps to disassemble protein aggregates that have accumulated due to stress (5, 4). Hsp104p has also been shown to interact with the co-chaperones Sti1p, Cpr7p, and Cns1p (11).

HSP104 is expressed at very low levels under normal conditions but is induced upon stress (12). Transcriptional upregulation is independently mediated by the transcriptional activators Msn2p/Msn4p and Hsf1p, which bind to three stress response elements and two heat shock elements present in the HSP104 promoter (13).

Hsp104p is thought to exist in either inactive monomeric, dimeric, or trimeric forms or as an active, ring-shaped hexamer (reviewed in 10). During aggregate disassembly, substrate proteins are unfolded and subsequently threaded through this hexameric ring (14). Formation of the Hsp104p hexamer is nucleotide-dependent and regulated by NBD2, one of two Hsp104p nucleotide-binding domains (NBDs) (reviewed in 10 and 15). Although ATP hydrolysis by NBD2 is slow, ATPase activity of the other NBD, NBD1, is very high and provides the energy necessary to drive protein disaggregation (16). The state of Hsp104p ATP/ADP binding also regulates substrate affinity, with the ADP-bound state having low and the ATP-bound state having high polypeptide affinity (17).

HSP104 null mutations result in no obvious phenotype under normal conditions, but when exposed to stresses such as heat, ethanol, and radiation, these mutants have a markedly decreased rate of survival (2, 18). Expression of Hsp78p, the mitochondrial homolog of Hsp104p, in the cytosol of these mutants rescues them from heat damage and restores thermotolerance to the cells (19).

The effect of HSP104 expression has also been studied in yeast models of human disease, such as the prion disease Creutzfeldt-Jakob disease (OMIM) and Huntington disease (OMIM). HSP104 deletion strains are unable to propagate the yeast prions [PSI+], [PIN+], and [URE3] (the mutant protein forms of Sup35p, Rnq1p, and Ure2p, respectively) and it has been shown that both overexpression and underexpression of Hsp104p cures cells carrying the [PSI+] prion (reviewed in 20). Overexpression of HSP104 has been shown to reduce polyglutamine aggregation and toxicity in mammalian cells and to extend the lifespan of transgenic Huntington mice (21 and references contained therein).

Hsp104p homologs have been identified in bacteria, other fungi, and plants (6, 22, 23).

Last updated: 2006-06-28 Contact SGD

References cited on this page View Complete Literature Guide for HSP104
1) Sanchez, Y. and Lindquist, S.  (1992) Personal Communication, Mortimer Map Edition 11
2) Sanchez Y, et al.  (1992) Hsp104 is required for tolerance to many forms of stress. EMBO J 11(6):2357-64
3) Chernoff YO, et al.  (1995) Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science 268(5212):880-4
4) Glover JR and Lindquist S  (1998) Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94(1):73-82
5) Parsell DA, et al.  (1994) Protein disaggregation mediated by heat-shock protein Hsp104. Nature 372(6505):475-8
6) Parsell DA, et al.  (1991) Hsp104 is a highly conserved protein with two essential nucleotide-binding sites. Nature 353(6341):270-3
7) Moriyama H, et al.  (2000) [URE3] prion propagation in Saccharomyces cerevisiae: requirement for chaperone Hsp104 and curing by overexpressed chaperone Ydj1p. Mol Cell Biol 20(23):8916-22
8) Tkach JM, et al.  (2012) Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress. Nat Cell Biol 14(9):966-76
9) Jackrel ME, et al.  (2014) Potentiated hsp104 variants antagonize diverse proteotoxic misfolding events. Cell 156(1-2):170-82
10) Bosl B, et al.  (2006) The molecular chaperone Hsp104-A molecular machine for protein disaggregation. J Struct Biol 156(1):139-48
11) Abbas-Terki T, et al.  (2001) Hsp104 interacts with Hsp90 cochaperones in respiring yeast. Mol Cell Biol 21(22):7569-75
12) Sanchez Y and Lindquist SL  (1990) HSP104 required for induced thermotolerance. Science 248(4959):1112-5
13) Grably MR, et al.  (2002) HSF and Msn2/4p can exclusively or cooperatively activate the yeast HSP104 gene. Mol Microbiol 44(1):21-35
14) Lum R, et al.  (2004) Evidence for an unfolding/threading mechanism for protein disaggregation by Saccharomyces cerevisiae Hsp104. J Biol Chem 279(28):29139-46
15) Burnie JP, et al.  (2006) Fungal heat-shock proteins in human disease. FEMS Microbiol Rev 30(1):53-88
16) Hattendorf DA and Lindquist SL  (2002) Cooperative kinetics of both Hsp104 ATPase domains and interdomain communication revealed by AAA sensor-1 mutants. EMBO J 21(1-2):12-21
17) Bosl B, et al.  (2005) Substrate binding to the molecular chaperone Hsp104 and its regulation by nucleotides. J Biol Chem 280(46):38170-6
18) Boreham DR and Mitchel RE  (1994) Regulation of heat and radiation stress responses in yeast by hsp-104. Radiat Res 137(2):190-5
19) Schmitt M, et al.  (1996) The molecular chaperone Hsp78 confers compartment-specific thermotolerance to mitochondria. J Cell Biol 134(6):1375-86
20) Jones GW and Tuite MF  (2005) Chaperoning prions: the cellular machinery for propagating an infectious protein? Bioessays 27(8):823-32
21) Vacher C, et al.  (2005) Overexpression of yeast hsp104 reduces polyglutamine aggregation and prolongs survival of a transgenic mouse model of Huntington's disease. Hum Mol Genet 14(22):3425-33
22) Zenthon JF, et al.  (2006) The [PSI+] prion of Saccharomyces cerevisiae can be propagated by an Hsp104 orthologue from Candida albicans. Eukaryot Cell 5(2):217-25
23) Schirmer EC, et al.  (1994) An Arabidopsis heat shock protein complements a thermotolerance defect in yeast. Plant Cell 6(12):1899-909