P38532 · HSF1_MOUSE

  • Protein
    Heat shock factor protein 1
  • Gene
    Hsf1
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Functions as a stress-inducible and DNA-binding transcription factor that plays a central role in the transcriptional activation of the heat shock response (HSR), leading to the expression of a large class of molecular chaperones, heat shock proteins (HSPs), that protect cells from cellular insult damage. In unstressed cells, is present in a HSP90-containing multichaperone complex that maintains it in a non-DNA-binding inactivated monomeric form. Upon exposure to heat and other stress stimuli, undergoes homotrimerization and activates HSP gene transcription through binding to site-specific heat shock elements (HSEs) present in the promoter regions of HSP genes. Upon heat shock stress, forms a chromatin-associated complex with TTC5/STRAP and p300/EP300 to stimulate HSR transcription, therefore increasing cell survival. Activation is reversible, and during the attenuation and recovery phase period of the HSR, returns to its unactivated form. Binds to inverted 5'-NGAAN-3' pentamer DNA sequences. Binds to chromatin at heat shock gene promoters. Activates transcription of transcription factor FOXR1 which in turn activates transcription of the heat shock chaperones HSPA1A and HSPA6 and the antioxidant NADPH-dependent reductase DHRS2 (By similarity).
Binds the promoter region upstream of exon 1 of Mpv17l to activate expression of the M-LPS isoform which is involved in metabolism of reactive oxygen species (PubMed:20231359).
Also serves several other functions independently of its transcriptional activity. Involved in the repression of Ras-induced transcriptional activation of the c-fos gene in heat-stressed cells. Positively regulates pre-mRNA 3'-end processing and polyadenylation of HSP70 mRNA upon heat-stressed cells in a symplekin (SYMPK)-dependent manner. Plays a role in nuclear export of stress-induced HSP70 mRNA. Plays a role in the regulation of mitotic progression. Also plays a role as a negative regulator of non-homologous end joining (NHEJ) repair activity in a DNA damage-dependent manner. Involved in stress-induced cancer cell proliferation in a IER5-dependent manner

GO annotations

AspectTerm
Cellular Componentcentrosome
Cellular Componentcytoplasm
Cellular Componentcytosol
Cellular Componentkinetochore
Cellular Componentmitotic spindle pole
Cellular Componentnuclear stress granule
Cellular Componentnucleoplasm
Cellular Componentnucleus
Cellular Componentperinuclear region of cytoplasm
Cellular ComponentPML body
Cellular Componentpronucleus
Cellular Componentprotein folding chaperone complex
Cellular Componentprotein-containing complex
Cellular Componentribonucleoprotein complex
Molecular Functionchromatin binding
Molecular Functionchromatin DNA binding
Molecular FunctionDNA binding
Molecular FunctionDNA-binding transcription activator activity, RNA polymerase II-specific
Molecular Functionheat shock protein binding
Molecular FunctionHsp90 protein binding
Molecular Functionidentical protein binding
Molecular Functionprotein heterodimerization activity
Molecular FunctionRNA polymerase II cis-regulatory region sequence-specific DNA binding
Molecular FunctionRNA polymerase II intronic transcription regulatory region sequence-specific DNA binding
Molecular Functionsequence-specific DNA binding
Molecular Functiontranslation elongation factor binding
Biological Processcell population proliferation
Biological Processcellular response to cadmium ion
Biological Processcellular response to copper ion
Biological Processcellular response to diamide
Biological Processcellular response to gamma radiation
Biological Processcellular response to heat
Biological Processcellular response to sodium arsenite
Biological Processcellular response to unfolded protein
Biological ProcessDNA repair
Biological Processembryonic placenta development
Biological Processembryonic process involved in female pregnancy
Biological Processepithelial cell proliferation
Biological Processfemale meiotic nuclear division
Biological Processin utero embryonic development
Biological ProcessMAPK cascade
Biological ProcessmRNA processing
Biological ProcessmRNA transport
Biological Processnegative regulation of double-strand break repair via nonhomologous end joining
Biological Processnegative regulation of epithelial cell proliferation
Biological Processnegative regulation of protein-containing complex assembly
Biological Processnegative regulation of transcription by RNA polymerase II
Biological Processnegative regulation of tumor necrosis factor production
Biological Processpositive regulation of cold-induced thermogenesis
Biological Processpositive regulation of gene expression
Biological Processpositive regulation of mitotic cell cycle
Biological Processpositive regulation of multicellular organism growth
Biological Processpositive regulation of transcription by RNA polymerase II
Biological Processprotein-containing complex assembly
Biological Processregulation of cellular response to heat
Biological Processresponse to heat
Biological Processresponse to lipopolysaccharide
Biological Processspermatogenesis

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Heat shock factor protein 1
  • Short names
    HSF 1
  • Alternative names
    • Heat shock transcription factor 1
      (HSTF 1)

Gene names

    • Name
      Hsf1

Organism names

  • Taxonomic identifier
  • Strains
    • WEHI-3
    • 129/SvJ
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus

Accessions

  • Primary accession
    P38532
  • Secondary accessions
    • O70462

Proteomes

Organism-specific databases

Subcellular Location

Nucleus
Cytoplasm
Nucleus, nucleoplasm
Note: The monomeric form is cytoplasmic in unstressed cells (PubMed:26159920).
Predominantly nuclear protein in both unstressed and heat shocked cells. Translocates in the nucleus upon heat shock. Nucleocytoplasmic shuttling protein. Colocalizes with IER5 in the nucleus. Colocalizes with BAG3 to the nucleus upon heat stress. Localizes in subnuclear granules called nuclear stress bodies (nSBs) upon heat shock. Colocalizes with SYMPK and SUMO1 in nSBs upon heat shock. Colocalizes with PRKACA/PKA in the nucleus and nSBs upon heat shock. Relocalizes from the nucleus to the cytoplasm during the attenuation and recovery phase period of the heat shock response. Translocates in the cytoplasm in a YWHAE- and XPO1/CRM1-dependent manner. Together with histone H2AX, redistributed in discrete nuclear DNA damage-induced foci after ionizing radiation (IR). Colocalizes with calcium-responsive transactivator SS18L1 at kinetochore region on the mitotic chromosomes. Colocalizes with gamma tubulin at centrosome. Localizes at spindle pole in metaphase. Colocalizes with PLK1 at spindle poles during prometaphase

Keywords

Phenotypes & Variants

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 24 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

Chemistry

PTM/Processing

Features

Showing features for modified residue, chain, cross-link.

TypeIDPosition(s)Description
Modified residue1N-acetylmethionine
ChainPRO_00001245681-525Heat shock factor protein 1
Modified residue80N6-acetyllysine
Modified residue91N6-acetyllysine; alternate
Cross-link91Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternate
Modified residue118N6-acetyllysine
Modified residue121Phosphoserine; by MAPKAPK2
Cross-link126Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)
Cross-link131Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)
Modified residue142Phosphothreonine; by CK2
Modified residue150N6-acetyllysine
Modified residue188N6-acetyllysine
Modified residue208N6-acetyllysine; alternate
Cross-link208Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternate
Modified residue216Phosphoserine; by PLK1
Cross-link224Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)
Modified residue230Phosphoserine; by CAMK2A
Modified residue275Phosphoserine
Modified residue292Phosphoserine
Modified residue298N6-acetyllysine; alternate
Cross-link298Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); alternate
Cross-link298Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternate
Modified residue303Phosphoserine
Modified residue307Phosphoserine
Modified residue314Phosphoserine
Modified residue319Phosphoserine
Modified residue320Phosphoserine; by PKA
Modified residue323Phosphothreonine
Modified residue326Phosphoserine; by MAPK12
Modified residue345Phosphoserine
Modified residue415Phosphoserine; by PLK1
Modified residue440Phosphoserine
Modified residue520N6-acetyllysine

Post-translational modification

Phosphorylated. Phosphorylated in unstressed cells; this phosphorylation is constitutive and implicated in the repression of HSF1 transcriptional activity. Phosphorylated on Ser-121 by MAPKAPK2; this phosphorylation promotes interaction with HSP90 proteins and inhibits HSF1 homotrimerization, DNA-binding and transactivation activities. Phosphorylation on Ser-303 by GSK3B/GSK3-beat and on Ser-307 by MAPK3 within the regulatory domain is involved in the repression of HSF1 transcriptional activity and occurs in a RAF1-dependent manner. Phosphorylation on Ser-303 and Ser-307 increases HSF1 nuclear export in a YWHAE- and XPO1/CRM1-dependent manner. Phosphorylation on Ser-307 is a prerequisite for phosphorylation on Ser-303. According to, Ser-303 is not phosphorylated in unstressed cells. Phosphorylated on Ser-415 by PLK1; phosphorylation promotes nuclear translocation upon heat shock. Hyperphosphorylated upon heat shock and during the attenuation and recovery phase period of the heat shock response. Phosphorylated on Thr-142; this phosphorylation increases HSF1 transactivation activity upon heat shock. Phosphorylation on Ser-230 by CAMK2A; this phosphorylation enhances HSF1 transactivation activity upon heat shock. Phosphorylation on Ser-326 by MAPK12; this phosphorylation enhances HSF1 nuclear translocation, homotrimerization and transactivation activities upon heat shock. Phosphorylated on Ser-320 by PRKACA/PKA; this phosphorylation promotes nuclear localization and transcriptional activity upon heat shock. Phosphorylated by MAPK8; this phosphorylation occurs upon heat shock, induces HSF1 translocation into nuclear stress bodies and negatively regulates transactivation activity. Neither basal nor stress-inducible phosphorylation on Ser-230, Ser-292, Ser-303, Ser-307, Ser-314, Ser-319, Ser-320, Thr-323, Ser-326, Ser-338, Ser-345, Ser-364 and Thr-365 within the regulatory domain is involved in the regulation of HSF1 subcellular localization or DNA-binding activity; however, it negatively regulates HSF1 transactivation activity. Phosphorylated on Ser-216 by PLK1 in the early mitotic period; this phosphorylation regulates HSF1 localization to the spindle pole, the recruitment of the SCF(BTRC) ubiquitin ligase complex inducing HSF1 degradation, and hence mitotic progression. Dephosphorylated on Ser-121, Ser-307, Ser-314 and Thr-323 by phosphatase PPP2CA in an IER5-dependent manner, leading to HSF1-mediated transactivation activity.
Sumoylated with SUMO1 and SUMO2 upon heat shock in a ERK2-dependent manner. Sumoylated by SUMO1 on Lys-298; sumoylation occurs upon heat shock and promotes its localization to nuclear stress bodies and DNA-binding activity. Phosphorylation on Ser-303 and Ser-307 is probably a prerequisite for sumoylation.
Acetylated on Lys-118; this acetylation is decreased in a IER5-dependent manner. Acetylated on Lys-118, Lys-208 and Lys-298; these acetylations occur in a EP300-dependent manner. Acetylated on Lys-80; this acetylation inhibits DNA-binding activity upon heat shock. Deacetylated on Lys-80 by SIRT1; this deacetylation increases DNA-binding activity.
Ubiquitinated by SCF(BTRC) and degraded following stimulus-dependent phosphorylation at Ser-216 by PLK1 in mitosis. Polyubiquitinated. Undergoes proteasomal degradation upon heat shock and during the attenuation and recovery phase period of the heat shock response.

Keywords

Proteomic databases

PTM databases

Expression

Gene expression databases

Interaction

Subunit

Monomer; cytoplasmic latent and transcriptionally inactive monomeric form in unstressed cells. Homotrimer; in response to stress, such as heat shock, homotrimerizes and translocates into the nucleus, binds to heat shock element (HSE) sequences in promoter of heat shock protein (HSP) genes and acquires transcriptional ability. Interacts (via monomeric form) with FKBP4; this interaction occurs in unstressed cells. Associates (via monomeric form) with HSP90 proteins in a multichaperone complex in unnstressed cell; this association maintains HSF1 in a non-DNA-binding and transcriptional inactive form by preventing HSF1 homotrimerization. Homotrimeric transactivation activity is modulated by protein-protein interactions and post-translational modifications. Interacts with HSP90AA1; this interaction is decreased in a IER5-dependent manner, promoting HSF1 accumulation in the nucleus, homotrimerization and DNA-binding activities. Part (via regulatory domain in the homotrimeric form) of a large heat shock-induced HSP90-dependent multichaperone complex at least composed of FKBP4, FKBP5, HSP90 proteins, PPID, PPP5C and PTGES3; this association maintains the HSF1 homotrimeric DNA-bound form in a transcriptionally inactive form. Interacts with BAG3 (via BAG domain); this interaction occurs in normal and heat-shocked cells promoting nuclear shuttling of HSF1 in a BAG3-dependent manner. Interacts (via homotrimeric and hyperphosphorylated form) with FKBP4; this interaction occurs upon heat shock in a HSP90-dependent multichaperone complex. Interacts (via homotrimeric form preferentially) with EEF1A proteins. In heat shocked cells, stress-denatured proteins compete with HSF1 homotrimeric DNA-bound form for association of the HSP90-dependent multichaperone complex, and hence alleviating repression of HSF1-mediated transcriptional activity. Interacts (via homotrimeric form preferentially) with DAXX; this interaction relieves homotrimeric HSF1 from repression of its transcriptional activity by HSP90-dependent multichaperone complex upon heat shock. Interacts (via D domain and preferentially with hyperphosphorylated form) with JNK1; this interaction occurs under both normal growth conditions and immediately upon heat shock. Interacts (via D domain and preferentially with hyperphosphorylated form) with MAPK3; this interaction occurs upon heat shock. Interacts with IER5 (via central region); this interaction promotes PPP2CA-induced dephosphorylation on Ser-121, Ser-307, Ser-314 and Thr-323 and HSF1 transactivation activity. Found in a ribonucleoprotein complex composed of the HSF1 homotrimeric form, translation elongation factor eEF1A proteins and non-coding RNA heat shock RNA-1 (HSR1); this complex occurs upon heat shock and stimulates HSF1 DNA-binding activity. Interacts (via transactivation domain) with HSPA1A/HSP70 and DNAJB1; these interactions result in the inhibition of heat shock- and HSF1-induced transcriptional activity during the attenuation and recovery phase from heat shock. Interacts (via Ser-303 and Ser-307 phosphorylated form) with YWHAE; this interaction promotes HSF1 sequestration in the cytoplasm in an ERK-dependent manner. Found in a complex with IER5 and PPP2CA. Interacts with TPR; this interaction increases upon heat shock and stimulates export of HSP70 mRNA. Interacts with SYMPK (via N-terminus) and CSTF2; these interactions occur upon heat shock. Interacts (via transactivation domain) with HSPA8. Interacts with EEF1D; this interaction occurs at heat shock promoter element (HSE) sequences. Interacts with MAPKAPK2. Interacts with PRKACA/PKA. Interacts (via transactivation domain) with GTF2A2. Interacts (via transactivation domain) with GTF2B. Interacts (via transactivation domain) with TBP. Interacts with CDK9, CCNT1 and EP300. Interacts (via N-terminus) with XRCC5 (via N-terminus) and XRCC6 (via N-terminus); these interactions are direct and prevent XRCC5/XRCC6 heterodimeric binding and non-homologous end joining (NHEJ) repair activities induced by ionizing radiation (IR). Interacts with PLK1; this interaction occurs during the early mitotic period, increases upon heat shock but does not modulate neither HSF1 homotrimerization and DNA-binding activities. Interacts (via Ser-216 phosphorylated form) with CDC20; this interaction occurs in mitosis in a MAD2L1-dependent manner and prevents PLK1-stimulated degradation of HSF1 by blocking the recruitment of the SCF(BTRC) ubiquitin ligase complex. Interacts with MAD2L1; this interaction occurs in mitosis. Interacts with BTRC; this interaction occurs during mitosis, induces its ubiquitin-dependent degradation following stimulus-dependent phosphorylation at Ser-216, a process inhibited by CDC20. Interacts with HSP90AA1 and HSP90AB1. Forms a complex with TTC5/STRAP and p300/EP300; these interactions augment chromatin-bound HSF1 and p300/EP300 histone acetyltransferase activity (By similarity).

Protein-protein interaction databases

Chemistry

Miscellaneous

Family & Domains

Features

Showing features for region, compositional bias, motif.

TypeIDPosition(s)Description
Region15-120DNA-binding domain
Region130-203Hydrophobic repeat HR-A/B
Region203-224D domain
Region221-310Regulatory domain
Region272-327Disordered
Compositional bias340-360Polar residues
Region340-365Disordered
Region367-525Transactivation domain
Region380-405Hydrophobic repeat HR-C
Motif408-4169aaTAD
Region441-460Disordered
Region495-525Disordered

Domain

In unstressed cells, spontaneous homotrimerization is inhibited. Intramolecular interactions between the hydrophobic repeat HR-A/B and HR-C regions are necessary to maintain HSF1 in the inactive, monomeric conformation. Furthermore, intramolecular interactions between the regulatory domain and the nonadjacent transactivation domain prevents transcriptional activation, a process that is relieved upon heat shock. The regulatory domain is necessary for full repression of the transcriptional activation domain in unstressed cells through its phosphorylation on Ser-303 and Ser-307. In heat stressed cells, HSF1 homotrimerization occurs through formation of a three-stranded coiled-coil structure generated by intermolecular interactions between HR-A/B regions allowing DNA-binding activity. The D domain is necessary for translocation to the nucleus, interaction with JNK1 and MAPK3 and efficient JNK1- and MAPK3-dependent phosphorylation. The regulatory domain confers heat shock inducibility on the transcriptional transactivation domain. The regulatory domain is necessary for transcriptional activation through its phosphorylation on Ser-230 upon heat shock. 9aaTAD is a transactivation motif present in a large number of yeast and animal transcription factors.

Sequence similarities

Belongs to the HSF family.

Phylogenomic databases

Family and domain databases

Sequence & Isoform

Align isoforms (2)
  • Sequence status
    Complete

This entry describes 2 isoforms produced by Alternative splicing.

P38532-1

This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

  • Length
    525
  • Mass (Da)
    57,223
  • Last updated
    2002-08-30 v2
  • Checksum
    DCB6418FC12F5F43
MDLAVGPGAAGPSNVPAFLTKLWTLVSDPDTDALICWSPSGNSFHVFDQGQFAKEVLPKYFKHNNMASFVRQLNMYGFRKVVHIEQGGLVKPERDDTEFQHPCFLRGQEQLLENIKRKVTSVSTLKSEDIKIRQDSVTRLLTDVQLMKGKQECMDSKLLAMKHENEALWREVASLRQKHAQQQKVVNKLIQFLISLVQSNRILGVKRKIPLMLSDSNSAHSVPKYGRQYSLEHVHGPGPYSAPSPAYSSSSLYSSDAVTSSGPIISDITELAPTSPLASPGRSIDERPLSSSTLVRVKQEPPSPPHSPRVLEASPGRPSSMDTPLSPTAFIDSILRESEPTPAASNTAPMDTTGAQAPALPTPSTPEKCLSVACLDKNELSDHLDAMDSNLDNLQTMLTSHGFSVDTSALLDLFSPSVTMPDMSLPDLDSSLASIQELLSPQEPPRPIEAENSNPDSGKQLVHYTAQPLFLLDPDAVDTGSSELPVLFELGESSYFSEGDDYTDDPTISLLTGTEPHKAKDPTVS

P38532-2

  • Name
    1
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical

Computationally mapped potential isoform sequences

There are 8 potential isoforms mapped to this entry

View all
EntryEntry nameGene nameLength
A0A2I3BR06A0A2I3BR06_MOUSEHsf1218
A0A2I3BQV9A0A2I3BQV9_MOUSEHsf1142
A0A2I3BQX3A0A2I3BQX3_MOUSEHsf1172
A0A2I3BRL6A0A2I3BRL6_MOUSEHsf1107
A0A2I3BS48A0A2I3BS48_MOUSEHsf178
A0A075F5C6A0A075F5C6_MOUSEHsf1531
A0A2R8W6L8A0A2R8W6L8_MOUSEHsf1438
Q52L52Q52L52_MOUSEHsf1477

Features

Showing features for compositional bias, alternative sequence.

TypeIDPosition(s)Description
Compositional bias340-360Polar residues
Alternative sequenceVSP_002416413-434in isoform 1

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
X61753
EMBL· GenBank· DDBJ
CAA43892.1
EMBL· GenBank· DDBJ
mRNA
BC013716
EMBL· GenBank· DDBJ
AAH13716.1
EMBL· GenBank· DDBJ
mRNA
AF059275
EMBL· GenBank· DDBJ
AAC80425.1
EMBL· GenBank· DDBJ
Genomic DNA

Genome annotation databases

Similar Proteins

Disclaimer

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