HSPA2

Summary

HSPA2 (heat shock protein family A (Hsp70) member 2, HGNC:5235) is a protein-coding gene on chromosome 14q23.3, encoding Heat shock-related 70 kDa protein 2 (P54652). 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 comple….

Enables enzyme binding activity and unfolded protein binding activity. Involved in negative regulation of inclusion body assembly and protein refolding. Located in cytosol.

Source: NCBI Gene 3306 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 54 total
• Druggable target: yes
• MANE Select transcript: NM_021979

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5235
Approved symbol	HSPA2
Name	heat shock protein family A (Hsp70) member 2
Location	14q23.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000126803
Ensembl biotype	protein_coding
OMIM	140560
Entrez	3306

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000247207, ENST00000394709, ENST00000554883

RefSeq mRNA: 2 — MANE Select: NM_021979 NM_001387931, NM_021979

CCDS: CCDS9766

Canonical transcript exons

ENST00000247207 — 1 exons

Exon	Start	End
ENSE00000867595	64540741	64543237

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.8970 / max 1650.2384, expressed in 1368 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140117	30.8602	1364
140114	0.0368	9

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
inferior vagus X ganglion	UBERON:0005363	99.60	gold quality
middle frontal gyrus	UBERON:0002702	99.44	gold quality
subthalamic nucleus	UBERON:0001906	99.36	gold quality
lateral globus pallidus	UBERON:0002476	99.30	gold quality
globus pallidus	UBERON:0001875	99.19	gold quality
medulla oblongata	UBERON:0001896	99.19	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.17	gold quality
medial globus pallidus	UBERON:0002477	99.13	gold quality
superior vestibular nucleus	UBERON:0007227	99.13	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.12	gold quality
inferior olivary complex	UBERON:0002127	99.05	gold quality
corpus callosum	UBERON:0002336	99.05	gold quality
pons	UBERON:0000988	99.00	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.94	gold quality
CA1 field of hippocampus	UBERON:0003881	98.93	gold quality
spinal cord	UBERON:0002240	98.89	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.87	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.83	gold quality
renal medulla	UBERON:0000362	98.73	gold quality
adult organism	UBERON:0007023	98.70	gold quality
substantia nigra pars compacta	UBERON:0001965	98.68	gold quality
ventral tegmental area	UBERON:0002691	98.63	gold quality
biceps brachii	UBERON:0001507	98.57	gold quality
olfactory bulb	UBERON:0002264	98.23	gold quality
vastus lateralis	UBERON:0001379	98.16	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.04	gold quality
triceps brachii	UBERON:0001509	98.03	gold quality
hair follicle	UBERON:0002073	97.97	gold quality
right testis	UBERON:0004534	97.91	gold quality
decidua	UBERON:0002450	97.89	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	80.01
E-CURD-114	yes	61.30
E-GEOD-135922	yes	25.94
E-GEOD-84465	yes	11.24
E-GEOD-110499	no	20.05
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFAT5

Literature-anchored findings (GeneRIF, showing 39)

• The HspA2 gene was down-regulated in sperm from infertile men with idiopathic oligoteratozoospermia, suggesting that such anomalies of gene expression might be associated with pathogenesis in some subtypes of male infertility. (PMID:16517558)
• This is the first report on HSPA2 gene expression in ejaculated spermatozoa from adolescents and its relationship with varicocele pathology. (PMID:17007855)
• Delineation of the minimal promoter is a basic step toward identifying the cis and trans elements involved in the regulation of the HSPA2 gene expression, especially in cancer cells. (PMID:17369882)
• results indicate that the there may be no association of the HSP70-2 gene polymorphism with ankylosing spondylitis in Chinese Han population (PMID:17922431)
• The HspA2, like Hsp70 protein, can be involved in protecting nucleoli and centrosomes integrity in cancer cells subjected to heat shock and, possibly, other cellular stressors. (PMID:18452162)
• GDF15, HSPA2, TMEFF2, and VIM were identified as epigenetic biomarkers for Bladder cancer. (PMID:20975101)
• The results clearly show that certain human tissues constitutively express varying levels of HSPA2 protein in a highly differentiated way. (PMID:21373891)
• It appears that polymorphism of HSP70-2 gene is not directly associated with the susceptibility to peptic ulcer diseases but BB genotype is associated with an increased risk of duodenal ulcer in older subjects in the Japanese population. (PMID:22353510)
• In somatic cells HSPA2 can be a part of a system protecting cells against cytotoxic stimuli inducing proteotoxic stress. (PMID:22397456)
• Heat-shock protein A2(HSPA2) expression significantly correlates with sperm concentration and morphology thus aberrant HSPA2 expression may play an important role in capacitation and fertilisation processes (PMID:22670834)
• The interaction between SPAM1, ARSA and HSPA2 in a multimeric complex mediating sperm-egg interaction. (PMID:23209833)
• HSPA2 regulates the expression of sperm surface receptors involved in human sperm-oocyte recognition, such as arylsulfatase A and SPAM1. (PMID:23247813)
• Its single nucleotide polymorphism is associated with severityof Crohn’s disease. (PMID:23425104)
• Overexpression of HSPA2 is correlated with esophageal squamous cell carcinoma. (PMID:23777267)
• findings show polymorphisms of HSP70 genes are associated with the development of gastric cancer and duodenal ulcers in a population at high risk for gastric cancer in Costa Rica (PMID:24051039)
• Genotype analysis of HSP70-2 (+1267 A/G) polymorphism revealed a significant association between the minor allele G and presence of Multiple Sclerosis (PMID:24485944)
• High HSPA2 expression is associated with non-small cell lung carcinoma. (PMID:24922646)
• HSP70-2 +1267 polymorphism may influence the risk of coronary artery disease (CAD) in Iranian population, however further studies are needed to clarify the role of other HSP70-2 gene polymorphisms in the pathogenesis of the CAD. (PMID:25108126)
• High expression of HSPA2 is associated with hepatocellular carcinoma. (PMID:25117073)
• The fertilization rate with ICSI is associated with HspA2 expression in the testis from which sperm retrieved and the alteration of HspA2 expression has been involved in spermatogenic impairment. (PMID:25308252)
• we consider the evidence supporting the role of HSPA2 in sperm function and explore the potential mechanisms by which it is depleted in the spermatozoa of infertile patients–{REVIEW} (PMID:25865850)
• Results suggest that overexpression of HSPA2 in pancreatic cancer is associated with aggressive progression and poor prognosis and that HSPA2 may be served as a prognostic marker. (PMID:25890028)
• HSPA2 expression increased under conditions that stimulated HIF-1alpha activity, whereas inhibition of HIF-1alpha abrogated hypoxia-induced up-regulation of HSPA2 expression (PMID:26164067)
• ACE and PDIA6 were identified as potential HSPA2-interacting proteins; this assemblage resides in membrane raft microdomains located in the peri-acrosomal region of the sperm head. (PMID:26676989)
• The data suggest that seminal plasma HSPA2 Cell-free mRNA is different between asthenozoospermic and normozoospermic individuals and it might be an indicator for semen quality. (PMID:27209630)
• This study showed that a strong association between rs2227956 polymorphism and MS risk, which is independent from the association with HSP70-2 rs1061581, and a significant link between hsp70-hom protein expression and multiple sclerosis severity. (PMID:27609295)
• HSPA2 may play an important role in tumor progression, and serve as a potential biomarker for the prediction of adverse prognosis in pancreatic carcinoma (PMID:28416384)
• HSPA2 appears to be necessary for controlling development of properly stratified epidermis and thus for maintenance of skin homeostasis. (PMID:28786487)
• Assessing the potential of HSPA2 and ADAM2 as two biomarkers for human sperm selection. (PMID:30463455)
• An increased level of the HSP70 gene expression in peripheral blood leukocytes in mothers with a life-threatening disease of their child indicates the damaging effect of long-lasting psychoemotional stress at the cellular level and activation of the protective reaction mediated by HSP70. (PMID:30726658)
• RNF144A functions as a tumor suppressor in breast cancer through ubiquitin ligase activity-dependent regulation of stability and oncogenic functions of HSPA2. (PMID:31406303)
• Functional redundancy of HSPA1, HSPA2 and other HSPA proteins in non-small cell lung carcinoma (NSCLC); an implication for NSCLC treatment. (PMID:31591429)
• Human sperm chaperone HSPA2 distribution during in vitro capacitation. (PMID:33246276)
• Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE epsilon2 protective effect in Alzheimer disease. (PMID:34480088)
• Paternal factors in recurrent pregnancy loss: an insight through analysis of non-synonymous single-nucleotide polymorphism in human testis-specific chaperone HSPA2 gene. (PMID:34845642)
• Evaluation of seminal plasma HSPA2 protein as a biomarker of human spermatogenesis status. (PMID:34959194)
• Tumorigenic and immunological roles of Heat shock protein A2 in pancreatic cancer: a bioinformatics analysis. (PMID:35649069)
• HSPA1A, HSPA2, and HSPA8 Are Potential Molecular Biomarkers for Prognosis among HSP70 Family in Alzheimer’s Disease. (PMID:36246562)
• The human testis-enriched HSPA2 interacts with HIF-1alpha in epidermal keratinocytes, yet HIF-1alpha stability and HIF-1-dependent gene expression rely on the HSPA (HSP70) activity. (PMID:38641179)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	hsp70.3	ENSDARG00000021924
danio_rerio	hsp70.1	ENSDARG00000029688
danio_rerio	hsp70l	ENSDARG00000055723
danio_rerio	hspa1b	ENSDARG00000056210
danio_rerio	hsp70.2	ENSDARG00000092362
mus_musculus	Hspa2	ENSMUSG00000059970
rattus_norvegicus	Hspa2	ENSRNOG00000006472
drosophila_melanogaster	Hsc70-1	FBGN0001216
drosophila_melanogaster	Hsc70-4	FBGN0266599
caenorhabditis_elegans		WBGENE00002005

Paralogs (13): HSPA5 (ENSG00000044574), HSPA8 (ENSG00000109971), HSPA9 (ENSG00000113013), HSPH1 (ENSG00000120694), HYOU1 (ENSG00000149428), HSPA13 (ENSG00000155304), HSPA4L (ENSG00000164070), HSPA4 (ENSG00000170606), HSPA6 (ENSG00000173110), HSPA14 (ENSG00000187522), HSPA1B (ENSG00000204388), HSPA1A (ENSG00000204389), HSPA1L (ENSG00000204390)

Protein

Protein identifiers

Heat shock-related 70 kDa protein 2 — P54652 (reviewed: P54652)

Alternative names: Heat shock protein family A member 2

All UniProt accessions (1): P54652

UniProt curated annotations — full annotation on UniProt →

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 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. Plays a role in spermatogenesis. In association with SHCBP1L may participate in the maintenance of spindle integrity during meiosis in male germ cells.

Subunit / interactions. Interacts with FKBP6. Interacts with ZNF541. Component of the CatSper complex. Interacts with RABL2/RABL2A; binds preferentially to GTP-bound RABL2. Interacts with SHCBP1L; this interaction may promote the recruitment of HSPA2 to the spindle.

Subcellular location. Cytoplasm. Cytoskeleton. Spindle.

Domain organisation. 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.

Similarity. Belongs to the heat shock protein 70 family.

RefSeq proteins (2): NP_001374860, NP_068814* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013126	Hsp_70_fam	Family
IPR018181	Heat_shock_70_CS	Conserved_site
IPR029047	HSP70_peptide-bd_sf	Homologous_superfamily
IPR029048	HSP70_C_sf	Homologous_superfamily
IPR043129	ATPase_NBD	Homologous_superfamily

Pfam: PF00012

UniProt features (61 total): strand 18, helix 16, turn 6, binding site 5, modified residue 4, sequence conflict 4, region of interest 3, sequence variant 2, chain 1, mutagenesis site 1, compositionally biased region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3I33	X-RAY DIFFRACTION	1.3
4FSV	X-RAY DIFFRACTION	1.8
5FPE	X-RAY DIFFRACTION	1.96
5FPM	X-RAY DIFFRACTION	1.96
5FPN	X-RAY DIFFRACTION	1.96
5FPD	X-RAY DIFFRACTION	1.97

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54652-F1	89.50	0.66

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (5): 13–16; 72; 205–207; 271–278; 342–345

Post-translational modifications (4): 403, 408, 414, 564

Mutagenesis-validated functional residues (1):

Position	Phenotype
564	abolishes methylation by mettl21a.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1221632	Meiotic synapsis
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-3371497	HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand
R-HSA-3371568	Attenuation phase
R-HSA-9833482	PKR-mediated signaling

MSigDB gene sets: 307 (showing top): GOBP_CHROMOSOME_ORGANIZATION, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RESPONSE_TO_COLD, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, REACTOME_MEIOTIC_SYNAPSIS, KEGG_MAPK_SIGNALING_PATHWAY, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOCC_CELL_SURFACE, BROWNE_HCMV_INFECTION_16HR_UP, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, GOBP_MALE_GAMETE_GENERATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (12): response to unfolded protein (GO:0006986), male meiotic nuclear division (GO:0007140), male meiosis I (GO:0007141), spermatogenesis (GO:0007283), spermatid development (GO:0007286), response to heat (GO:0009408), response to cold (GO:0009409), positive regulation of G2/M transition of mitotic cell cycle (GO:0010971), protein refolding (GO:0042026), synaptonemal complex disassembly (GO:0070194), negative regulation of inclusion body assembly (GO:0090084), cell differentiation (GO:0030154)

GO Molecular Function (13): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), enzyme binding (GO:0019899), heat shock protein binding (GO:0031072), protein folding chaperone (GO:0044183), tau protein binding (GO:0048156), obsolete unfolded protein binding (GO:0051082), protein-folding chaperone binding (GO:0051087), glycolipid binding (GO:0051861), disordered domain specific binding (GO:0097718), ATP-dependent protein folding chaperone (GO:0140662), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (14): synaptonemal complex (GO:0000795), male germ cell nucleus (GO:0001673), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), CatSper complex (GO:0036128), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), meiotic spindle (GO:0072687), spindle (GO:0005819), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Meiosis	1
Cellular response to heat stress	1
Cellular responses to stress	1
HSF1-dependent transactivation	1
Antimicrobial mechanism of IFN-stimulated genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
male gamete generation	3
protein binding	3
meiotic cell cycle	2
response to stress	2
response to temperature stimulus	2
protein folding	2
ATP-dependent activity	2
intracellular membraneless organelle	2
response to topologically incorrect protein	1
meiotic nuclear division	1
meiosis I	1
male meiotic nuclear division	1
developmental process involved in reproduction	1
germ cell development	1
spermatid differentiation	1
G2/M transition of mitotic cell cycle	1
regulation of G2/M transition of mitotic cell cycle	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of cell cycle G2/M phase transition	1
cellular component disassembly	1
synaptonemal complex organization	1
negative regulation of cellular component organization	1
inclusion body assembly	1
regulation of inclusion body assembly	1
cellular developmental process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
molecular_function	1
cytoskeletal protein binding	1
lipid binding	1
carbohydrate derivative binding	1
protein domain specific binding	1
protein folding chaperone	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
synaptonemal structure	1
germ cell nucleus	1

Protein interactions and networks

STRING

4097 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSPA2	CATSPERB	Q9H7T0	838
HSPA2	SPAM1	P38567	754
HSPA2	CATSPER1	Q8NEC5	742
HSPA2	ARSA	P15289	626
HSPA2	HSP90AB1	P08238	626
HSPA2	TIMM44	O43615	601
HSPA2	KCTD19	Q17RG1	529
HSPA2	CDC37	Q16543	524
HSPA2	PCGF6	Q9BYE7	519
HSPA2	SHCBP1L	Q9BZQ2	496
HSPA2	TOMM70	O94826	494
HSPA2	BAG5	Q9UL15	490
HSPA2	HSP90AA1	P07900	478
HSPA2	PDIA6	Q15084	474
HSPA2	PPID	Q08752	468
HSPA2	OLR1	P78380	468

IntAct

446 interactions, top by confidence:

A	B	Type	Score
HSPBP1	HSPA2	psi-mi:“MI:0915”(physical association)	0.920
HSPA2	HSPBP1	psi-mi:“MI:0915”(physical association)	0.920
HSPA8	BAG2	psi-mi:“MI:2364”(proximity)	0.860
IFT70B	IFT56	psi-mi:“MI:0914”(association)	0.790
HSPA8	GAK	psi-mi:“MI:0914”(association)	0.760
BAG4	HSPA2	psi-mi:“MI:0915”(physical association)	0.700
TRIM38	HSPA2	psi-mi:“MI:0915”(physical association)	0.670
HSPA2	TRIM38	psi-mi:“MI:0915”(physical association)	0.670
HSPA2	FGF21	psi-mi:“MI:0915”(physical association)	0.610
GABPB1	HSPA2	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	MAP3K5	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	MIP	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	NEUROD1	psi-mi:“MI:0915”(physical association)	0.560
PER1	HSPA2	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	SSB	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	ZNF124	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	FOSL1	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	DPF1	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	ASH2L	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	DNAJA3	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	SOCS6	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	PSMF1	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	TSPAN2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (561): HSPA2 (Affinity Capture-MS), TRIM38 (Two-hybrid), HSPBP1 (Two-hybrid), HSPA2 (Affinity Capture-MS), HSPA2 (Affinity Capture-MS), HSPA2 (Affinity Capture-MS), HSPBP1 (Two-hybrid), HSPA2 (Co-fractionation), HSPA2 (Co-fractionation), HSPA2 (Co-fractionation), HSPA2 (Co-fractionation), HSPA2 (Co-fractionation), STIP1 (Co-fractionation), HSPA2 (Affinity Capture-MS), HSPA2 (Affinity Capture-MS)

ESM2 similar proteins: A2Q0Z1, O59855, O65719, O73885, P02827, P08106, P08108, P08418, P09446, P0DMV8, P0DMV9, P0DMW0, P0DMW1, P11142, P11147, P14659, P17156, P19120, P19378, P22953, P27541, P34930, P34933, P36415, P41753, P47773, P53421, P53623, P54652, P63017, P63018, Q01233, Q01877, Q05944, Q06248, Q10265, Q27965, Q27975, Q4U0F3, Q557E0

Diamond homologs: A0A0D1CD96, A0A509AJG0, A2Q0Z1, A5A8V7, F5HB71, G3I8R9, J9VZ70, O24581, O59855, O73885, O93866, P02827, P06761, P07823, P08108, P08418, P09189, P0CB32, P0DMV8, P0DMV9, P10591, P10592, P11021, P11142, P14659, P16474, P17156, P17879, P19120, P19208, P19378, P20029, P20163, P22010, P22202, P24067, P26413, P27420, P29844, P34933

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HSPA2	down-regulates	MAP3K5	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 124 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of HSF1-mediated heat shock response	7	12.2×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	9	8.9×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

54 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	0
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

209 predictions. Top by Δscore:

Variant	Effect	Δscore
14:64535974:GT:G	donor_gain	1.0000
14:64535971:G:GT	donor_gain	0.9900
14:64535971:GAAGT:G	donor_gain	0.9900
14:64535976:G:GG	donor_gain	0.9900
14:64535976:G:A	donor_loss	0.9700
14:64535977:T:G	donor_loss	0.9700
14:64535978:G:GC	donor_loss	0.9600
14:64535980:G:C	donor_loss	0.9600
14:64535971:G:T	donor_gain	0.9500
14:64535979:A:AC	donor_loss	0.9500
14:64535972:AAGT:A	donor_gain	0.9400
14:64536096:GCACA:G	donor_gain	0.9000
14:64540843:AGT:A	acceptor_gain	0.8900
14:64545284:G:GC	acceptor_gain	0.8700
14:64535973:AGT:A	donor_gain	0.8600
14:64535974:GTG:G	donor_gain	0.8600
14:64535975:TGT:T	donor_gain	0.8600
14:64535976:GTG:G	donor_gain	0.8600
14:64536101:G:GG	donor_gain	0.8400
14:64540844:G:T	acceptor_gain	0.8400
14:64545283:T:TA	acceptor_gain	0.8400
14:64542786:GC:G	donor_gain	0.8200
14:64536100:A:AG	donor_gain	0.8000
14:64545280:TTTTG:T	acceptor_gain	0.7900
14:64540843:A:AG	acceptor_gain	0.7600
14:64540844:G:GG	acceptor_gain	0.7600
14:64540841:TCAG:T	acceptor_gain	0.7500
14:64542764:GAC:G	donor_gain	0.7500
14:64545281:TTTG:T	acceptor_gain	0.7400
14:64545282:TTG:T	acceptor_gain	0.7300

AlphaMissense

4220 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:64540886:G:C	G13R	1.000
14:64540887:G:A	G13D	1.000
14:64540887:G:T	G13V	1.000
14:64540890:C:T	T14I	1.000
14:64540907:G:T	G20W	1.000
14:64540945:C:A	N32K	1.000
14:64540945:C:G	N32K	1.000
14:64540970:A:C	S41R	1.000
14:64540972:C:A	S41R	1.000
14:64540972:C:G	S41R	1.000
14:64541006:G:C	G53R	1.000
14:64541007:G:A	G53D	1.000
14:64541007:G:T	G53V	1.000
14:64541016:C:A	A56D	1.000
14:64541065:G:C	K72N	1.000
14:64541065:G:T	K72N	1.000
14:64541067:G:C	R73T	1.000
14:64541067:G:T	R73M	1.000
14:64541068:G:C	R73S	1.000
14:64541068:G:T	R73S	1.000
14:64541076:G:A	G76E	1.000
14:64541289:T:A	V147D	1.000
14:64541292:C:A	P148Q	1.000
14:64541295:C:A	A149D	1.000
14:64541300:T:C	F151L	1.000
14:64541302:C:A	F151L	1.000
14:64541302:C:G	F151L	1.000
14:64541314:G:C	Q155H	1.000
14:64541314:G:T	Q155H	1.000
14:64541315:C:A	R156S	1.000

dbSNP variants (sampled 300 via entrez): RS1000287320 (14:64539846 T>A), RS1000646288 (14:64533908 A>G,T), RS1001128738 (14:64535346 T>C), RS1001860111 (14:64538832 G>T), RS1002539400 (14:64535996 T>C), RS1002656494 (14:64537032 C>T), RS1003033681 (14:64536754 A>C), RS1003536509 (14:64537485 G>T), RS1003588720 (14:64537228 C>T), RS1004213703 (14:64534585 A>T), RS1004266523 (14:64533992 C>T), RS1004478522 (14:64540093 G>A), RS1005246529 (14:64543227 T>C), RS1005317442 (14:64537970 G>A,C), RS1005599023 (14:64537703 T>A)

Disease associations

OMIM: gene MIM:140560 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90000025_536	Appendicular lean mass	3.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2062348 (SINGLE PROTEIN), CHEMBL4523664 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Heat shock proteins

ChEMBL bioactivities

19 potent at pChembl≥5 of 28 total, top 19 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.66	Ki	220	nM	CHEMBL4519613
6.60	Ki	250	nM	CHEMBL4545529
6.28	Ki	520	nM	CHEMBL4545529
6.16	IC50	700	nM	CHEMBL5410116
5.85	Ki	1400	nM	CHEMBL4556409
5.70	Ki	2000	nM	CHEMBL4556409
5.60	Ki	2500	nM	CHEMBL4556409
5.48	Ki	3300	nM	CHEMBL4519613
5.46	Ki	3500	nM	CHEMBL4593659
5.45	Ki	3548	nM	CHEMBL4593659
5.43	Ki	3700	nM	CHEMBL4583945
5.33	Ki	4700	nM	CHEMBL4519613
5.22	IC50	6000	nM	CHEMBL5409255
5.19	IC50	6430	nM	CHEMBL4473449
5.17	IC50	6800	nM	CHEMBL5435048
5.16	Ki	6900	nM	CHEMBL4545529
5.14	Ki	7200	nM	CHEMBL4583945
5.10	Ki	8000	nM	CHEMBL4452822
5.00	Ki	1e+04	nM	CHEMBL4545529

PubChem BioAssay actives

23 with measured affinity, of 129 total; 12 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[[(2R,3S,4R,5R)-5-[6-amino-8-[(3,4-dichlorophenyl)methylamino]purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methoxymethyl]benzonitrile	1617534: Covalent inhibition of HSP72-NBD (unknown origin) nucleotide-derived FP probe displacement based by fluorescence polarization assay	ki	0.1995	uM
[(2R,3S,4R,5R)-5-[6-amino-8-(quinolin-6-ylmethylamino)purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methyl 4-fluorosulfonylbenzoate	1617537: Covalent inhibition of HSP72-NBD (unknown origin) after 1 hr nucleotide-derived FP probe displacement based by fluorescence polarization assay	ki	0.2000	uM
4-[[(2R,3S,4R,5R)-5-[6-amino-8-[(4-chlorophenyl)methylamino]purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methoxymethyl]benzonitrile	1617534: Covalent inhibition of HSP72-NBD (unknown origin) nucleotide-derived FP probe displacement based by fluorescence polarization assay	ki	0.2000	uM
[(2R,3S,4R,5R)-5-[6-amino-8-[(4-chlorophenyl)methylamino]purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methyl 4-fluorosulfonylbenzoate	1617535: Covalent inhibition of HSP72-NBD (unknown origin) after 2 hrs nucleotide-derived FP probe displacement based by fluorescence polarization assay	ki	0.2500	uM
N-[(2S,3R)-1-[(4,5-dimethyl-1,3-thiazol-2-yl)amino]-3-methyl-1-oxopentan-2-yl]-1H-indole-2-carboxamide	1968961: Inhibition of HspA2 (unknown origin) by FP assay	ic50	0.7000	uM
(4-fluorophenyl) 4-[[(2R,3S,4R,5R)-5-[6-amino-8-[(4-chlorophenyl)methylamino]purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methoxymethyl]benzoate	1617536: Covalent inhibition of HSP72-NBD (unknown origin) after 24 hrs nucleotide-derived FP probe displacement based by fluorescence polarization assay	ki	1.4000	uM
[(2R,3S,4R,5R)-5-[6-amino-8-[(4-chlorophenyl)methylamino]purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methyl 4-cyanobenzoate	1617534: Covalent inhibition of HSP72-NBD (unknown origin) nucleotide-derived FP probe displacement based by fluorescence polarization assay	ki	3.5000	uM
3-[(2R,3S,4R,5R)-5-[6-amino-8-[(4-chlorophenyl)methylamino]purin-9-yl]-3,4-dihydroxyoxolan-2-yl]propyl prop-2-enoate	1617533: Covalent inhibition of HSP72-NBD (unknown origin) after 46 hrs nucleotide-derived FP probe displacement based by fluorescence polarization assay	ki	3.7000	uM
N-[(2S,3S)-3-methyl-1-oxo-1-(1,3-thiazol-2-ylamino)pentan-2-yl]thiophene-2-carboxamide	1968961: Inhibition of HspA2 (unknown origin) by FP assay	ic50	6.0000	uM
(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2,6-diaminohexanoyl]amino]acetyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]propanoyl]amino]propanoic acid	1573978: Inhibition of (2S,8S,11S,14S)-2-(4-aminobutyl)-14-(3-guanidinopropyl)-8-(4-hydroxybenzyl)-11-(hydroxymethyl)-4,7,10,13,16,32-hexaoxo-36-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-19,22,25,28-tetraoxa-3,6,9,12,15,31-hexaazahexatriacontan-1-oic acid binding to human Hsp72 SBD expressed in Escherichia coli BL21 (DE3) by Western blot analysis	ic50	6.4300	uM
N-[(2S)-1-oxo-3-phenyl-1-(1,3-thiazol-2-ylamino)propan-2-yl]thiophene-2-carboxamide	1968961: Inhibition of HspA2 (unknown origin) by FP assay	ic50	6.8000	uM
[(2R,3S,4R,5R)-5-[6-amino-8-(methylamino)purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methyl 4-fluorosulfonylbenzoate	1617537: Covalent inhibition of HSP72-NBD (unknown origin) after 1 hr nucleotide-derived FP probe displacement based by fluorescence polarization assay	ki	8.0000	uM

CTD chemical–gene interactions

126 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
sodium arsenite	affects cotreatment, increases expression	6
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	4
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	4
Cadmium Chloride	increases abundance, increases expression, affects expression, decreases expression	4
Cannabidiol	decreases expression, increases expression, affects cotreatment	3
Cisplatin	increases expression, affects cotreatment	3
Lipopolysaccharides	affects cotreatment, decreases expression, affects expression, affects response to substance	3
bisphenol A	decreases expression, increases expression	2
trichostatin A	affects expression, increases expression	2
entinostat	affects cotreatment, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Troglitazone	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Dexamethasone	increases expression, affects cotreatment	2
Fluorouracil	increases expression, affects response to substance	2
Nickel	decreases expression	2
Quercetin	affects binding, decreases expression	2
Rotenone	decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Okadaic Acid	increases expression	2
tert-Butylhydroperoxide	decreases expression	2
Particulate Matter	increases abundance, decreases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
alpha phellandrene	increases expression	1
propionaldehyde	increases expression	1
geraniol	decreases expression	1

ChEMBL screening assays

37 unique, capped per target: 37 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2065196	Binding	Binding affinity to HSPA2 in human Jurkat cells at 150 uM followed by UV irradiation for 30 mins with Wood’s glass filtered medium pressure mercury arc light after cell lysis measured after denaturing wash by SDS-PAGE based pull down assay	Biotinylated quercetin as an intrinsic photoaffinity proteomics probe for the identification of quercetin target proteins. — Bioorg Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1NB	Abcam K-562 HSPA2 KO	Cancer cell line	Female
CVCL_D2JW	Abcam Raji HSPA2 KO	Cancer cell line	Male
CVCL_E0EG	Ubigene HeLa HSPA2 KO	Cancer cell line	Female
CVCL_UQ77	Abcam Jurkat HSPA2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.