HSPA1A (heat shock protein family A (Hsp70) member 1A)

Gene

• Entrez ID: 3303
• Gene name: Heat shock protein family A (Hsp70) member 1A
• Gene symbol: HSPA1A
• Synonyms: HEL-S-103, HSP70-1, HSP70-1A, HSP70-2, HSP70.1, HSP70.2, HSP70I, HSP72, HSPA1
• Chromosome: 6
• Chromosome location: 6p21.33
• Summary: This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family. In conjuction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins. [provided by RefSeq, Jul 2008]

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT000866	hsa-miR-15a-5p	Microarray	18362358
MIRT001456	hsa-miR-16-5p	Microarray	18362358
MIRT001456	hsa-miR-16-5p	pSILAC, Proteomics	18668040
MIRT018150	hsa-miR-335-5p	Microarray	18185580
MIRT021244	hsa-miR-146a-5p	Microarray	18057241
MIRT025302	hsa-miR-34a-5p	Proteomics	21566225
MIRT100353	hsa-miR-223-5p	PAR-CLIP	22012620
MIRT100356	hsa-miR-4424	PAR-CLIP	22012620
MIRT100357	hsa-miR-4682	PAR-CLIP	22012620
MIRT525026	hsa-miR-496	PAR-CLIP	22012620
MIRT525027	hsa-miR-6735-3p	PAR-CLIP	22012620
MIRT525028	hsa-miR-595	PAR-CLIP	22012620

Transcription factors

Transcription factor	Regulation	Reference
FOXA1	Activation	19486887
HSF1	Unknown	17897941;20692357;23212905;23874968
XBP1	Unknown	17404501

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0001618	Function	Virus receptor activity	IEA
GO:0001664	Function	G protein-coupled receptor binding	IDA	12150907
GO:0003714	Function	Transcription corepressor activity	IDA	9499401
GO:0003723	Function	RNA binding	HDA	22658674, 22681889
GO:0005102	Function	Signaling receptor binding	IPI	24790089
GO:0005515	Function	Protein binding	IPI	9222587, 9499401, 12853476, 15603737, 15671022, 17357109, 17616579, 18975920, 19933325, 20223214, 20625543, 21044950, 21081504, 22219199, 22528486, 23349634, 23812373, 23892143, 23973223, 24318877, 24338975, 24428437, 24613385, 25156257, 25959826, 26496610, 27133716, 27137183, 27708
GO:0005524	Function	ATP binding	IBA	21873635
GO:0005524	Function	ATP binding	IDA	23921388
GO:0005576	Component	Extracellular region	TAS
GO:0005634	Component	Nucleus	IBA	21873635
GO:0005634	Component	Nucleus	IDA	10205060, 17167422
GO:0005654	Component	Nucleoplasm	TAS
GO:0005737	Component	Cytoplasm	IBA	21873635
GO:0005737	Component	Cytoplasm	IDA	9553041, 11785981, 24061851, 24790089
GO:0005737	Component	Cytoplasm	TAS	16130169
GO:0005739	Component	Mitochondrion	TAS	16130169
GO:0005783	Component	Endoplasmic reticulum	TAS	16130169
GO:0005813	Component	Centrosome	IDA	27137183
GO:0005814	Component	Centriole	IDA	24061851
GO:0005829	Component	Cytosol	IBA	21873635
GO:0005829	Component	Cytosol	IDA	21231916
GO:0005829	Component	Cytosol	TAS
GO:0005886	Component	Plasma membrane	IBA	21873635
GO:0005925	Component	Focal adhesion	HDA	21423176
GO:0006402	Process	MRNA catabolic process	IDA	10205060
GO:0006986	Process	Response to unfolded protein	IDA
GO:0007041	Process	Lysosomal transport	ISS
GO:0008180	Component	COP9 signalosome	IBA	21873635
GO:0008180	Component	COP9 signalosome	IDA	18850735
GO:0008285	Process	Negative regulation of cell population proliferation	IMP	9553041
GO:0010628	Process	Positive regulation of gene expression	IMP	25281747
GO:0010941	Process	Regulation of cell death	IMP	21231916
GO:0016192	Process	Vesicle-mediated transport	IBA	21873635
GO:0016234	Component	Inclusion body	IDA	15603737
GO:0016235	Component	Aggresome	IDA	15885686
GO:0016607	Component	Nuclear speck	IDA	9553041
GO:0016887	Function	ATPase activity	IBA	21873635
GO:0016887	Function	ATPase activity	IDA	21231916, 23921388
GO:0019899	Function	Enzyme binding	IPI	23921388
GO:0030308	Process	Negative regulation of cell growth	IMP	9553041
GO:0030512	Process	Negative regulation of transforming growth factor beta receptor signaling pathway	IMP	24613385
GO:0031072	Function	Heat shock protein binding	IBA	21873635
GO:0031072	Function	Heat shock protein binding	IPI	17182002, 21231916, 23921388
GO:0031249	Function	Denatured protein binding	IPI	21909508
GO:0031396	Process	Regulation of protein ubiquitination	IDA	16809764
GO:0031397	Process	Negative regulation of protein ubiquitination	IDA	12150907
GO:0031625	Function	Ubiquitin protein ligase binding	IBA	21873635
GO:0031625	Function	Ubiquitin protein ligase binding	IPI	12150907, 15603737
GO:0031982	Component	Vesicle	HDA	19190083
GO:0032436	Process	Positive regulation of proteasomal ubiquitin-dependent protein catabolic process	IBA	21873635
GO:0032436	Process	Positive regulation of proteasomal ubiquitin-dependent protein catabolic process	IDA	24613385
GO:0032757	Process	Positive regulation of interleukin-8 production	IMP	24790089
GO:0032991	Component	Protein-containing complex	IDA	23349634
GO:0033120	Process	Positive regulation of RNA splicing	IDA	20625543
GO:0034599	Process	Cellular response to oxidative stress	TAS	24252804
GO:0034605	Process	Cellular response to heat	IDA	24061851
GO:0034620	Process	Cellular response to unfolded protein	IBA	21873635
GO:0034620	Process	Cellular response to unfolded protein	IMP	20625543
GO:0042026	Process	Protein refolding	IBA	21873635
GO:0042026	Process	Protein refolding	IDA	15603737, 21231916
GO:0042026	Process	Protein refolding	IMP	27708256
GO:0042826	Function	Histone deacetylase binding	IPI	16809764
GO:0043066	Process	Negative regulation of apoptotic process	IMP	17167422
GO:0043066	Process	Negative regulation of apoptotic process	TAS	16130169
GO:0043312	Process	Neutrophil degranulation	TAS
GO:0043488	Process	Regulation of mRNA stability	TAS
GO:0044183	Function	Protein folding chaperone	IBA	21873635
GO:0044183	Function	Protein folding chaperone	IDA	15603737
GO:0045296	Function	Cadherin binding	HDA	25468996
GO:0045648	Process	Positive regulation of erythrocyte differentiation	IMP	17167422
GO:0046034	Process	ATP metabolic process	IDA	23921388
GO:0046718	Process	Viral entry into host cell	IEA
GO:0047485	Function	Protein N-terminus binding	IPI	9553041
GO:0048471	Component	Perinuclear region of cytoplasm	IDA	10205060, 15603737
GO:0050821	Process	Protein stabilization	IDA	21909508
GO:0050821	Process	Protein stabilization	IMP	24790089
GO:0050821	Process	Protein stabilization	TAS	24252804
GO:0051082	Function	Unfolded protein binding	IBA	21873635
GO:0051082	Function	Unfolded protein binding	IDA	21231916
GO:0051082	Function	Unfolded protein binding	NAS	12150907
GO:0051082	Function	Unfolded protein binding	TAS	16130169
GO:0051085	Process	Chaperone cofactor-dependent protein refolding	IBA	21873635
GO:0051092	Process	Positive regulation of NF-kappaB transcription factor activity	IMP	24790089
GO:0051131	Process	Chaperone-mediated protein complex assembly	IDA	10811660
GO:0051787	Function	Misfolded protein binding	IBA	21873635
GO:0051787	Function	Misfolded protein binding	IDA	28842558
GO:0055131	Function	C3HC4-type RING finger domain binding	IPI	25281747
GO:0060548	Process	Negative regulation of cell death	IMP	21231916
GO:0070062	Component	Extracellular exosome	HDA	19199708, 20458337, 23533145
GO:0070370	Process	Cellular heat acclimation	IMP	21231916
GO:0070434	Process	Positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway	IMP	24790089
GO:0072562	Component	Blood microparticle	HDA	22516433
GO:0090063	Process	Positive regulation of microtubule nucleation	IMP	27137183
GO:0090084	Process	Negative regulation of inclusion body assembly	IDA	15603737, 21231916
GO:0097201	Process	Negative regulation of transcription from RNA polymerase II promoter in response to stress	IDA	9499401
GO:0097718	Function	Disordered domain specific binding	IPI	11785981
GO:1900034	Process	Regulation of cellular response to heat	TAS
GO:1901029	Process	Negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway	IDA	20625543
GO:1901673	Process	Regulation of mitotic spindle assembly	IBA	21873635
GO:1901673	Process	Regulation of mitotic spindle assembly	IMP	27137183
GO:1902236	Process	Negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	IDA	12150907, 20625543
GO:1902380	Process	Positive regulation of endoribonuclease activity	IDA	20625543
GO:1903265	Process	Positive regulation of tumor necrosis factor-mediated signaling pathway	IMP	24790089
GO:1904813	Component	Ficolin-1-rich granule lumen	TAS
GO:1990904	Component	Ribonucleoprotein complex	IDA	17289661
GO:2001240	Process	Negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	IMP	17167422

Other IDs

• MIM: 140550
• HGNC: 5232
• e!Ensembl: ENSG00000204389

Protein

• UniProt ID: P0DMV8
• Protein name: Heat shock 70 kDa protein 1A (Heat shock 70 kDa protein 1) (HSP70-1) (HSP70.1)
• Protein function: 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, 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 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. It goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release. The co-chaperones are of three types: J-domain co-chaperones such as 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 (PubMed:24012426, PubMed:26865365, PubMed:24318877). Maintains protein homeostasis during cellular stress through two opposing mechanisms: protein refolding and degradation. Its acetylation/deacetylation state determines whether it functions in protein refolding or protein degradation by controlling the competitive binding of co-chaperones HOPX and STUB1. During the early stress response, the acetylated form binds to HOPX which assists in chaperone-mediated protein refolding, thereafter, it is deacetylated and binds to ubiquitin ligase STUB1 that promotes ubiquitin-mediated protein degradation (PubMed:27708256). Regulates centrosome integrity during mitosis, and is required for the maintenance of a functional mitotic centrosome that supports the assembly of a bipolar mitotic spindle (PubMed:27137183). Enhances STUB1-mediated SMAD3 ubiquitination and degradation and facilitates STUB1-mediated inhibition of TGF-beta signaling (PubMed:24613385). Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223). Negatively regulates heat shock-induced HSF1 transcriptional activity during the attenuation and recovery phase period of the heat shock response (PubMed:9499401). Involved in the clearance of misfolded PRDM1/Blimp-1 proteins. Sequesters them in the cytoplasm and promotes their association with SYNV1/HRD1, leading to proteasomal degradation (PubMed:28842558). ; (Microbial infection) In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell.
• PDB: 1HJO, 1S3X, 1XQS, 2E88, 2E8A, 2LMG, 3A8Y, 3ATU, 3ATV, 3AY9, 3D2E, 3D2F, 3JXU, 3LOF, 3Q49, 4IO8, 4J8F, 4PO2, 4WV5, 4WV7, 5AQW, 5AQX, 5AQY, 5AQZ, 5AR0, 5BN8, 5BN9, 5BPL, 5BPM, 5BPN, 5GJJ, 5MKR, 5MKS, 5XI9, 5XIR, 6FHK, 6G3R, 6G3S, 6JPV, 6K39
• UniProt ID: P0DMV9
• Protein name: Heat shock 70 kDa protein 1B (Heat shock 70 kDa protein 2) (HSP70-2) (HSP70.2)
• Protein function: 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, 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 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. It goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release. The co-chaperones are of three types: J-domain co-chaperones such as 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 (PubMed:24012426, PubMed:26865365, PubMed:24318877). Maintains protein homeostasis during cellular stress through two opposing mechanisms: protein refolding and degradation. Its acetylation/deacetylation state determines whether it functions in protein refolding or protein degradation by controlling the competitive binding of co-chaperones HOPX and STUB1. During the early stress response, the acetylated form binds to HOPX which assists in chaperone-mediated protein refolding, thereafter, it is deacetylated and binds to ubiquitin ligase STUB1 that promotes ubiquitin-mediated protein degradation (PubMed:27708256). Regulates centrosome integrity during mitosis, and is required for the maintenance of a functional mitotic centrosome that supports the assembly of a bipolar mitotic spindle (PubMed:27137183). Enhances STUB1-mediated SMAD3 ubiquitination and degradation and facilitates STUB1-mediated inhibition of TGF-beta signaling (PubMed:24613385). Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223). ; (Microbial infection) In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell.
• PDB: 4J8F, 6FDT
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00012	HSP70	6 → 612	Hsp70 protein	Family

• Sequence:

  MAKAAAIGIDLGTTYSCVGVFQHGKVEIIANDQGNRTTPSYVAFTDTERLIGDAAKNQVA
  LNPQNTVFDAKRLIGRKFGDPVVQSDMKHWPFQVINDGDKPKVQVSYKGETKAFYPEEIS
  SMVLTKMKEIAEAYLGYPVTNAVITVPAYFNDSQRQATKDAGVIAGLNVLRIINEPTAAA
  IAYGLDRTGKGERNVLIFDLGGGTFDVSILTIDDGIFEVKATAGDTHLGGEDFDNRLVNH
  FVEEFKRKHKKDISQNKRAVRRLRTACERAKRTLSSSTQASLEIDSLFEGIDFYTSITRA
  RFEELCSDLFRSTLEPVEKALRDAKLDKAQIHDLVLVGGSTRIPKVQKLLQDFFNGRDLN
  KSINPDEAVAYGAAVQAAILMGDKSENVQDLLLLDVAPLSLGLETAGGVMTALIKRNSTI
  PTKQTQIFTTYSDNQPGVLIQVYEGERAMTKDNNLLGRFELSGIPPAPRGVPQIEVTFDI
  DANGILNVTATDKSTGKANKITITNDKGRLSKEEIERMVQEAEKYKAEDEVQRERVSAKN
  ALESYAFNMKSAVEDEGLKGKISEADKKKVLDKCQEVISWLDANTLAEKDEFEHKRKELE
  QVCNPIISGLYQGAGGPGPGGFGAQGPKGGSGSGPTIEEVD

• Sequence length: 641

Pathways

KEGG:

Spliceosome
MAPK signaling pathway
Protein processing in endoplasmic reticulum
Endocytosis
Longevity regulating pathway - multiple species
Antigen processing and presentation
Estrogen signaling pathway
Prion disease
Legionellosis
Toxoplasmosis
Measles
Lipid and atherosclerosis

Reactome:

Viral RNP Complexes in the Host Cell Nucleus
Regulation of HSF1-mediated heat shock response
HSP90 chaperone cycle for steroid hormone receptors (SHR)
Attenuation phase
HSF1-dependent transactivation
AUF1 (hnRNP D0) binds and destabilizes mRNA
Neutrophil degranulation

Associated diseases

Causal
Disease name	Disease term	dbSNP ID	References
Parkinson disease	Parkinson Disease	rs116074753, rs118203903, rs118203904, rs115735611, rs33939927, rs35801418, rs34805604, rs35870237, rs34995376, rs74315355, rs28940284, rs74315356, rs74315357, rs28940285, rs730880302, rs750664040, rs-1, rs74315359, rs74315360, rs45539432, rs74315361, rs119451946, rs80356771, rs74500255, rs75822236, rs1141814, rs78973108, rs121908681, rs121908686, rs121908687, rs137853054, rs137853055, rs137853056, rs137853057, rs137853058, rs137853059, rs34424986, rs137853060, rs397518439, rs28938172, rs74315351, rs74315353, rs137853051, rs118192098, rs121917767, rs121918104, rs1589451049, rs104893877, rs104893878, rs283413, rs112176450, rs111290936, rs188286943, rs387906863, rs387906864, rs774631197, rs199935023, rs387906942, rs397514694, rs398122403, rs398122404, rs398122405, rs104886460, rs409652, rs431905511, rs63751392, rs756677845, rs864309527, rs864309650, rs750014782, rs1554391082, rs864622011, rs869312810, rs869312809, rs869312811, rs369100678, rs879253853, rs869320761, rs747506979, rs879255630, rs886039854, rs191486604, rs781442277, rs1060499619, rs751037529, rs55777503, rs768091663, rs34208370, rs1553122929, rs772786691, rs754809877, rs1555907463, rs1557561340, rs781600849, rs141263564, rs1557901552, rs777160388, rs756783990, rs867929413, rs1237637353, rs1005937012, rs755000580, rs747427602, rs1578089802, rs771586218, rs748142049, rs1582953433, rs746646126, rs771529549, rs121918106	15585408
Schizophrenia	Schizophrenia	rs74315508, rs74315509, rs13447324, rs1558507406, rs387906932, rs387906933, rs-1, rs863223354, rs863223355, rs776061422, rs863223349, rs748809996, rs759748655, rs863223353, rs863223350, rs863223356, rs781821239, rs863223348, rs863223346, rs863223347, rs863223351, rs863223352, rs61734270, rs797045205, rs869312829, rs869312830, rs770913157, rs869312832, rs869312831, rs781720548, rs1262969313	15963589, 23893339, 17568569, 18299791, 19439993
Prostate cancer	Malignant neoplasm of prostate	rs121909139, rs121909140, rs121909141, rs121909142, rs121909143, rs606231169, rs606231170, rs137852584, rs137852578, rs137852580, rs137852581, rs137852582	15764345
Melanoma	melanoma	rs121913315, rs121913323, rs137853080, rs137853081, rs121909232, rs121913388, rs-1, rs104894094, rs1563902635, rs104894095, rs104894097, rs104894098, rs104894099, rs104894109, rs137854599, rs11547328, rs104894340, rs398123152, rs587780668, rs587782083, rs587782206, rs587782792, rs180177042, rs121913381, rs730881675, rs730881674, rs730881677, rs730881673, rs1800586, rs768966657, rs587778189, rs786204195, rs121913321, rs45476696, rs864622636, rs864622263, rs869025340, rs876660436, rs876658534, rs876658556, rs878853647, rs878853644, rs878853650, rs886041162, rs121913389, rs1057519852, rs121913384, rs121913387, rs1060501266, rs1060501263, rs1060501262, rs749714198, rs1060501265, rs559848002, rs1064794292, rs1131691187, rs1131691186, rs199907548, rs1554654052, rs1554656411, rs1554656624, rs1554653915, rs1554653956, rs1554656253, rs1554654224, rs754806883, rs1057520039, rs1563889584, rs1563889685, rs1287464120, rs1563888944, rs1563892715, rs1563889847, rs141798398, rs1587332338, rs1587340291, rs11552823, rs561034503, rs138677674, rs1819962958, rs1820531050	26984758
Chronic obstructive pulmonary disease	Chronic Obstructive Airway Disease	rs-1

Unknown
Disease name	Disease term	dbSNP ID	References
Mental depression	Major depression, single episode, Unipolar Depression, Major Depressive Disorder	rs587778876, rs587778877	17428599, 10092532, 12763290
Kidney failure	Kidney Failure, Acute		19546256, 12690470
Myocardial ischemia	Myocardial Ischemia		16214533
Pancreatic ductal carcinoma	Carcinoma, Pancreatic Ductal		17234771
Paranoid schizophrenia	Paranoid Schizophrenia		23893339
Prostatic neoplasms	Prostatic Neoplasms		15764345
Acute kidney insufficiency	Acute Kidney Insufficiency		19546256, 12690470