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Protein

Heat shock cognate 71 kDa protein

Gene

Hspa8

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, activation of proteolysis of misfolded proteins and the formation and dissociation of protein complexes. Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation. This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. The co-chaperones have been shown to not only regulate different steps of the ATPase cycle of HSP70, but they also have an individual specificity such that one co-chaperone may promote folding of a substrate while another may promote degradation. The affinity of HSP70 for polypeptides is regulated by its nucleotide bound state. In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. HSP70 goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release. The HSP70-associated co-chaperones are of three types: J-domain co-chaperones HSP40s (stimulate ATPase hydrolysis by HSP70), the nucleotide exchange factors (NEF) such as BAG1/2/3 (facilitate conversion of HSP70 from the ADP-bound to the ATP-bound state thereby promoting substrate release), and the TPR domain chaperones such as HOPX and STUB1. Acts as a repressor of transcriptional activation. Inhibits the transcriptional coactivator activity of CITED1 on Smad-mediated transcription. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. May have a scaffolding role in the spliceosome assembly as it contacts all other components of the core complex. Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion. Participates in the ER-associated degradation (ERAD) quality control pathway in conjunction with J domain-containing co-chaperones and the E3 ligase STUB1.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei71ATPBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi12 – 15ATPBy similarity4
Nucleotide bindingi202 – 204ATPBy similarity3
Nucleotide bindingi268 – 275ATPBy similarity8
Nucleotide bindingi339 – 342ATPBy similarity4

GO - Molecular functioni

GO - Biological processi

  • ATP metabolic process Source: MGI
  • cellular protein complex disassembly Source: MGI
  • chaperone cofactor-dependent protein refolding Source: MGI
  • chaperone-mediated autophagy Source: ParkinsonsUK-UCL
  • chaperone-mediated autophagy translocation complex disassembly Source: ParkinsonsUK-UCL
  • chaperone-mediated protein transport involved in chaperone-mediated autophagy Source: MGI
  • clathrin coat disassembly Source: MGI
  • late endosomal microautophagy Source: ParkinsonsUK-UCL
  • modulation by host of viral process Source: AgBase
  • mRNA processing Source: UniProtKB-KW
  • negative regulation of supramolecular fiber organization Source: MGI
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation by host of viral genome replication Source: AgBase
  • positive regulation of mRNA splicing, via spliceosome Source: MGI
  • protein folding Source: MGI
  • protein refolding Source: ParkinsonsUK-UCL
  • protein targeting to lysosome involved in chaperone-mediated autophagy Source: MGI
  • regulation of cell cycle Source: MGI
  • regulation of protein complex stability Source: ParkinsonsUK-UCL
  • regulation of protein stability Source: MGI
  • RNA splicing Source: UniProtKB-KW
  • transcription, DNA-templated Source: UniProtKB-KW

Keywordsi

Molecular functionChaperone, Repressor
Biological processmRNA processing, mRNA splicing, Stress response, Transcription, Transcription regulation
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-MMU-3371453 Regulation of HSF1-mediated heat shock response
R-MMU-3371497 HSP90 chaperone cycle for steroid hormone receptors (SHR)
R-MMU-3371568 Attenuation phase
R-MMU-3371571 HSF1-dependent transactivation
R-MMU-432720 Lysosome Vesicle Biogenesis
R-MMU-432722 Golgi Associated Vesicle Biogenesis
R-MMU-450408 AUF1 (hnRNP D0) binds and destabilizes mRNA
R-MMU-6798695 Neutrophil degranulation
R-MMU-72163 mRNA Splicing - Major Pathway
R-MMU-8856828 Clathrin-mediated endocytosis
R-MMU-8876725 Protein methylation
R-MMU-888590 GABA synthesis, release, reuptake and degradation

Names & Taxonomyi

Protein namesi
Recommended name:
Heat shock cognate 71 kDa protein
Alternative name(s):
Heat shock 70 kDa protein 8
Gene namesi
Name:Hspa8
Synonyms:Hsc70, Hsc73
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:105384 Hspa8

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus, Spliceosome

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000782712 – 646Heat shock cognate 71 kDa proteinAdd BLAST645

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineBy similarity1
Modified residuei108N6-acetyllysineCombined sources1
Modified residuei153PhosphoserineBy similarity1
Modified residuei246N6-acetyllysineCombined sources1
Modified residuei319N6-acetyllysine; alternateCombined sources1
Modified residuei319N6-succinyllysine; alternateCombined sources1
Modified residuei328N6-acetyllysineCombined sources1
Modified residuei329PhosphoserineBy similarity1
Modified residuei362PhosphoserineBy similarity1
Modified residuei469Omega-N-methylarginineCombined sources1
Modified residuei512N6-acetyllysine; alternateCombined sources1
Modified residuei512N6-succinyllysine; alternateCombined sources1
Cross-linki512Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1); alternateBy similarity
Cross-linki512Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternateBy similarity
Modified residuei524N6-acetyllysineCombined sources1
Modified residuei541PhosphoserineBy similarity1
Modified residuei561N6,N6,N6-trimethyllysine; alternate1 Publication1
Modified residuei561N6,N6,N6-trimethyllysine; by METTL21A; alternateBy similarity1
Modified residuei561N6,N6-dimethyllysine; alternateBy similarity1
Modified residuei589N6-acetyllysineBy similarity1
Modified residuei597N6-acetyllysineBy similarity1
Modified residuei601N6-acetyllysineCombined sources1

Post-translational modificationi

Acetylated.By similarity
ISGylated.1 Publication
Trimethylation at Lys-561 reduces fibrillar SNCA binding.By similarity

Keywords - PTMi

Acetylation, Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP63017
MaxQBiP63017
PaxDbiP63017
PeptideAtlasiP63017
PRIDEiP63017

2D gel databases

COMPLUYEAST-2DPAGEiP63017
REPRODUCTION-2DPAGEiIPI00323357
P63017
Q6NZD0
SWISS-2DPAGEiP63017
UCD-2DPAGEiP63017

PTM databases

CarbonylDBiP63017
iPTMnetiP63017
PhosphoSitePlusiP63017
SwissPalmiP63017

Expressioni

Tissue specificityi

Ubiquitous.

Inductioni

Constitutively synthesized.

Gene expression databases

BgeeiENSMUSG00000015656
CleanExiMM_HSPA8
ExpressionAtlasiP63017 baseline and differential
GenevisibleiP63017 MM

Interactioni

Subunit structurei

Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with PACRG. Interacts with DNAJC7. Interacts with DNAJB12 (via J domain). Interacts with DNAJB14 (via J domain). Interacts (via C-terminus) with the E3 ligase STUB1 forming a 210 kDa complex of one STUB1 and two HSPA8 molecules. Interacts with CITED1 (via N-terminus); the interaction suppresses the association of CITED1 to p300/CBP and Smad-mediated transcription transactivation. Component of the PRP19-CDC5L splicing complex composed of a core complex comprising a homotetramer of PRPF19, CDC5L, PLRG1 and BCAS2, and at least three less stably associated proteins CTNNBL1, CWC15 and HSPA8. Interacts with IRAK1BP1 and HSPH1/HSP105 (PubMed:9675148, PubMed:15292236, PubMed:17233114). Interacts with TRIM5. Part of a complex composed at least of ASCL2, EMSY, HCFC1, HSPA8, CCAR2, MATR3, MKI67, RBBP5, TUBB2A, WDR5 and ZNF335; this complex may have a histone H3-specific methyltransferase activity. Following LPS binding, may form a complex with CXCR4, GDF5 and HSP90AA1. Interacts with PRKN. Interacts with FOXP3. Interacts with DNAJC9 (via J domain). Interacts with MLLT11. Interacts with RNF207. Interacts with DNAJC21. Interacts with DNAJB2. Interacts with TTC1 (via TPR repeats). Interacts with SGTA (via TPR repeats). Interacts with HSF1 (via transactivation domain). Interacts with HOPX, STUB1, HSP40, HSP90, BAG2 and BAG3 (By similarity). Interacts with DNAJC12 (By similarity).By similarity3 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi200428, 48 interactors
CORUMiP63017
DIPiDIP-32353N
IntActiP63017, 47 interactors
MINTiP63017
STRINGi10090.ENSMUSP00000015800

Structurei

Secondary structure

1646
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi7 – 11Combined sources5
Beta strandi13 – 22Combined sources10
Beta strandi25 – 28Combined sources4
Beta strandi36 – 39Combined sources4
Beta strandi42 – 44Combined sources3
Beta strandi49 – 51Combined sources3
Helixi53 – 57Combined sources5
Turni58 – 61Combined sources4
Helixi63 – 65Combined sources3
Helixi70 – 72Combined sources3
Turni73 – 75Combined sources3
Helixi81 – 86Combined sources6
Turni87 – 89Combined sources3
Beta strandi91 – 97Combined sources7
Beta strandi100 – 107Combined sources8
Beta strandi110 – 114Combined sources5
Helixi116 – 135Combined sources20
Beta strandi141 – 146Combined sources6
Helixi152 – 164Combined sources13
Beta strandi168 – 174Combined sources7
Helixi175 – 182Combined sources8
Turni183 – 186Combined sources4
Beta strandi187 – 200Combined sources14
Beta strandi205 – 213Combined sources9
Beta strandi216 – 225Combined sources10
Helixi230 – 249Combined sources20
Helixi257 – 273Combined sources17
Turni274 – 276Combined sources3
Beta strandi278 – 288Combined sources11
Beta strandi291 – 298Combined sources8
Helixi299 – 312Combined sources14
Helixi314 – 324Combined sources11
Helixi328 – 330Combined sources3
Beta strandi333 – 338Combined sources6
Helixi339 – 342Combined sources4
Helixi344 – 353Combined sources10
Turni354 – 356Combined sources3
Turni365 – 367Combined sources3
Helixi368 – 380Combined sources13

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3CQXX-ray2.30A/B1-381[»]
ProteinModelPortaliP63017
SMRiP63017
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP63017

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni2 – 386Nucleotide-binding domain (NBD)By similarityAdd BLAST385
Regioni186 – 377Interaction with BAG1By similarityAdd BLAST192
Regioni394 – 509Substrate-binding domain (SBD)By similarityAdd BLAST116

Domaini

The N-terminal nucleotide binding domain (NBD) (also known as the ATPase domain) is responsible for binding and hydrolyzing ATP. The C-terminal substrate-binding domain (SBD) (also known as peptide-binding domain) binds to the client/substrate proteins. The two domains are allosterically coupled so that, when ATP is bound to the NBD, the SBD binds relatively weakly to clients. When ADP is bound in the NBD, a conformational change enhances the affinity of the SBD for client proteins.By similarity

Sequence similaritiesi

Belongs to the heat shock protein 70 family.Curated

Phylogenomic databases

eggNOGiKOG0101 Eukaryota
COG0443 LUCA
GeneTreeiENSGT00910000144045
HOVERGENiHBG051845
InParanoidiP63017
KOiK03283
OMAiAYTKNQD
OrthoDBiEOG091G03SF
PhylomeDBiP63017
TreeFamiTF105042

Family and domain databases

Gene3Di1.20.1270.10, 1 hit
2.60.34.10, 1 hit
InterProiView protein in InterPro
IPR018181 Heat_shock_70_CS
IPR029048 HSP70_C_sf
IPR029047 HSP70_peptide-bd_sf
IPR013126 Hsp_70_fam
PANTHERiPTHR19375 PTHR19375, 1 hit
PfamiView protein in Pfam
PF00012 HSP70, 1 hit
PRINTSiPR00301 HEATSHOCK70
SUPFAMiSSF100920 SSF100920, 1 hit
SSF100934 SSF100934, 1 hit
PROSITEiView protein in PROSITE
PS00297 HSP70_1, 1 hit
PS00329 HSP70_2, 1 hit
PS01036 HSP70_3, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P63017-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSKGPAVGID LGTTYSCVGV FQHGKVEIIA NDQGNRTTPS YVAFTDTERL
60 70 80 90 100
IGDAAKNQVA MNPTNTVFDA KRLIGRRFDD AVVQSDMKHW PFMVVNDAGR
110 120 130 140 150
PKVQVEYKGE TKSFYPEEVS SMVLTKMKEI AEAYLGKTVT NAVVTVPAYF
160 170 180 190 200
NDSQRQATKD AGTIAGLNVL RIINEPTAAA IAYGLDKKVG AERNVLIFDL
210 220 230 240 250
GGGTFDVSIL TIEDGIFEVK STAGDTHLGG EDFDNRMVNH FIAEFKRKHK
260 270 280 290 300
KDISENKRAV RRLRTACERA KRTLSSSTQA SIEIDSLYEG IDFYTSITRA
310 320 330 340 350
RFEELNADLF RGTLDPVEKA LRDAKLDKSQ IHDIVLVGGS TRIPKIQKLL
360 370 380 390 400
QDFFNGKELN KSINPDEAVA YGAAVQAAIL SGDKSENVQD LLLLDVTPLS
410 420 430 440 450
LGIETAGGVM TVLIKRNTTI PTKQTQTFTT YSDNQPGVLI QVYEGERAMT
460 470 480 490 500
KDNNLLGKFE LTGIPPAPRG VPQIEVTFDI DANGILNVSA VDKSTGKENK
510 520 530 540 550
ITITNDKGRL SKEDIERMVQ EAEKYKAEDE KQRDKVSSKN SLESYAFNMK
560 570 580 590 600
ATVEDEKLQG KINDEDKQKI LDKCNEIISW LDKNQTAEKE EFEHQQKELE
610 620 630 640
KVCNPIITKL YQSAGGMPGG MPGGFPGGGA PPSGGASSGP TIEEVD
Length:646
Mass (Da):70,871
Last modified:August 1, 1988 - v1
Checksum:i03A27B30E6C076ED
GO

Sequence cautioni

The sequence BAE31508 differs from that shown. Reason: Frameshift at positions 256 and 269.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti9I → V in BAE28187 (PubMed:16141072).Curated1
Sequence conflicti35N → K in BAE30081 (PubMed:16141072).Curated1
Sequence conflicti35N → K in BAE30861 (PubMed:16141072).Curated1
Sequence conflicti35N → K in BAE30753 (PubMed:16141072).Curated1
Sequence conflicti268E → G in BAE31432 (PubMed:16141072).Curated1
Sequence conflicti268E → G in BAE31346 (PubMed:16141072).Curated1
Sequence conflicti269R → G in BAE31508 (PubMed:16141072).Curated1
Sequence conflicti353F → C in BAE31664 (PubMed:16141072).Curated1
Sequence conflicti428F → L in AAA37869 (PubMed:3334718).Curated1
Sequence conflicti428F → L in AAB18391 (PubMed:10095055).Curated1
Sequence conflicti432S → Y in BAE30707 (PubMed:16141072).Curated1
Sequence conflicti589K → E in AAH66191 (PubMed:15489334).Curated1
Sequence conflicti645V → M in BAE30272 (PubMed:16141072).Curated1
Sequence conflicti645V → M in BAE31427 (PubMed:16141072).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M19141 mRNA Translation: AAA37869.1
U27129 mRNA Translation: AAC52836.1
U73744 Genomic DNA Translation: AAB18391.1
AK035286 mRNA Translation: BAC29016.1
AK075935 mRNA Translation: BAC36065.1
AK145579 mRNA Translation: BAE26523.1
AK146708 mRNA Translation: BAE27374.1
AK146985 mRNA Translation: BAE27588.1
AK147864 mRNA Translation: BAE28187.1
AK150474 mRNA Translation: BAE29591.1
AK150498 mRNA Translation: BAE29612.1
AK150701 mRNA Translation: BAE29780.1
AK150958 mRNA Translation: BAE29990.1
AK151065 mRNA Translation: BAE30081.1
AK151127 mRNA Translation: BAE30135.1
AK151287 mRNA Translation: BAE30272.1
AK151435 mRNA Translation: BAE30398.1
AK151516 mRNA Translation: BAE30465.1
AK151537 mRNA Translation: BAE30484.1
AK151775 mRNA Translation: BAE30681.1
AK151808 mRNA Translation: BAE30707.1
AK151865 mRNA Translation: BAE30753.1
AK151892 mRNA Translation: BAE30776.1
AK151948 mRNA Translation: BAE30822.1
AK151997 mRNA Translation: BAE30861.1
AK152598 mRNA Translation: BAE31346.1
AK152697 mRNA Translation: BAE31427.1
AK152703 mRNA Translation: BAE31432.1
AK152803 mRNA Translation: BAE31508.1 Frameshift.
AK153032 mRNA Translation: BAE31664.1
AK153834 mRNA Translation: BAE32204.1
AK159479 mRNA Translation: BAE35116.1
AK164000 mRNA Translation: BAE37581.1
AK166643 mRNA Translation: BAE38912.1
AK166721 mRNA Translation: BAE38970.1
AK166767 mRNA Translation: BAE39005.1
AK166776 mRNA Translation: BAE39012.1
AK166808 mRNA Translation: BAE39036.1
AK166830 mRNA Translation: BAE39053.1
AK166846 mRNA Translation: BAE39065.1
AK166861 mRNA Translation: BAE39076.1
AK166873 mRNA Translation: BAE39084.1
AK166908 mRNA Translation: BAE39109.1
AK166910 mRNA Translation: BAE39111.1
AK166913 mRNA Translation: BAE39113.1
AK166933 mRNA Translation: BAE39127.1
AK167043 mRNA Translation: BAE39211.1
AK167121 mRNA Translation: BAE39269.1
AK167122 mRNA Translation: BAE39270.1
AK167134 mRNA Translation: BAE39280.1
AK167163 mRNA Translation: BAE39304.1
AK167218 mRNA Translation: BAE39344.1
AK167229 mRNA Translation: BAE39353.1
AK167845 mRNA Translation: BAE39865.1
AK167910 mRNA Translation: BAE39917.1
AK168492 mRNA Translation: BAE40379.1
AK168519 mRNA Translation: BAE40398.1
AK168542 mRNA Translation: BAE40419.1
AK168711 mRNA Translation: BAE40553.1
AK168750 mRNA Translation: BAE40590.1
AK168776 mRNA Translation: BAE40612.1
AK168887 mRNA Translation: BAE40704.1
AK168934 mRNA Translation: BAE40745.1
AK169093 mRNA Translation: BAE40876.1
AK169179 mRNA Translation: BAE40957.1
AK169236 mRNA Translation: BAE41004.1
AK169293 mRNA Translation: BAE41049.1
BC006722 mRNA Translation: AAH06722.1
BC066191 mRNA Translation: AAH66191.1
BC085486 mRNA Translation: AAH85486.1
BC089322 mRNA Translation: AAH89322.1
BC089457 mRNA Translation: AAH89457.1
BC106193 mRNA Translation: AAI06194.1
X54401 Genomic DNA Translation: CAA38267.1
X54402 Genomic DNA Translation: CAA38268.1
X54403 Genomic DNA Translation: CAA38269.1
CCDSiCCDS23083.1
PIRiA45935
JC4853
RefSeqiNP_112442.2, NM_031165.4
UniGeneiMm.290774
Mm.336743
Mm.351377
Mm.412745
Mm.485345
Mm.486272

Genome annotation databases

EnsembliENSMUST00000015800; ENSMUSP00000015800; ENSMUSG00000015656
GeneIDi15481
KEGGimmu:15481
UCSCiuc009ozx.3 mouse

Similar proteinsi

Entry informationi

Entry nameiHSP7C_MOUSE
AccessioniPrimary (citable) accession number: P63017
Secondary accession number(s): P08109
, P12225, Q3U6R0, Q3U764, Q3U7D7, Q3U7E2, Q3U9B4, Q3U9G0, Q3UGM0, Q5FWJ6, Q62373, Q62374, Q62375, Q6NZD0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1988
Last sequence update: August 1, 1988
Last modified: March 28, 2018
This is version 148 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome
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Main funding by: National Institutes of Health