PDIA3

Summary

PDIA3 (protein disulfide isomerase family A member 3, HGNC:4606) is a protein-coding gene on chromosome 15q15.3, encoding Protein disulfide-isomerase A3 (P30101). Protein disulfide isomerase that catalyzes the formation, isomerization, and reduction or oxidation of disulfide bonds in client proteins and functions as a protein folding chaperone.

This gene encodes a protein of the endoplasmic reticulum that interacts with lectin chaperones calreticulin and calnexin to modulate folding of newly synthesized glycoproteins. The protein was once thought to be a phospholipase; however, it has been demonstrated that the protein actually has protein disulfide isomerase activity. It is thought that complexes of lectins and this protein mediate protein folding by promoting formation of disulfide bonds in their glycoprotein substrates. This protein also functions as a molecular chaperone that prevents the formation of protein aggregates.

Source: NCBI Gene 2923 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 103 total
• Druggable target: yes
• MANE Select transcript: NM_005313

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4606
Approved symbol	PDIA3
Name	protein disulfide isomerase family A member 3
Location	15q15.3
Locus type	gene with protein product
Status	Approved
Aliases	P58, ERp61, ERp57, ERp60, GRP57, PI-PLC, HsT17083
Ensembl gene	ENSG00000167004
Ensembl biotype	protein_coding
OMIM	602046
Entrez	2923

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 17 protein_coding, 11 nonsense_mediated_decay, 11 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000300289, ENST00000434494, ENST00000446523, ENST00000455250, ENST00000469684, ENST00000497349, ENST00000684793, ENST00000684837, ENST00000685864, ENST00000686175, ENST00000686227, ENST00000686314, ENST00000686374, ENST00000686402, ENST00000686929, ENST00000687167, ENST00000687173, ENST00000687211, ENST00000687465, ENST00000687665, ENST00000687794, ENST00000688330, ENST00000688652, ENST00000688851, ENST00000689152, ENST00000690271, ENST00000690274, ENST00000690371, ENST00000691274, ENST00000691893, ENST00000692341, ENST00000692484, ENST00000693281, ENST00000891521, ENST00000891522, ENST00000891523, ENST00000891524, ENST00000891525, ENST00000891526, ENST00000940337

RefSeq mRNA: 1 — MANE Select: NM_005313 NM_005313

CCDS: CCDS10101

Canonical transcript exons

ENST00000300289 — 13 exons

Exon	Start	End
ENSE00001145733	43771105	43773278
ENSE00001489318	43746438	43746706
ENSE00003488413	43763077	43763206
ENSE00003517848	43770250	43770329
ENSE00003522564	43770523	43770580
ENSE00003530840	43766728	43766910
ENSE00003534718	43761424	43761531
ENSE00003550998	43756649	43756766
ENSE00003555553	43768489	43768597
ENSE00003561751	43753824	43753902
ENSE00003617153	43769518	43769646
ENSE00003623036	43765450	43765566
ENSE00003653611	43765887	43766012

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 446.3175 / max 3701.5407, expressed in 1828 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146341	444.9812	1828
146342	1.3362	823

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.77	gold quality
stromal cell of endometrium	CL:0002255	99.58	gold quality
caput epididymis	UBERON:0004358	99.57	gold quality
type B pancreatic cell	CL:0000169	99.54	gold quality
left lobe of thyroid gland	UBERON:0001120	99.48	gold quality
right lobe of thyroid gland	UBERON:0001119	99.43	gold quality
thyroid gland	UBERON:0002046	99.43	gold quality
adenohypophysis	UBERON:0002196	99.37	gold quality
islet of Langerhans	UBERON:0000006	99.33	gold quality
pituitary gland	UBERON:0000007	99.33	gold quality
smooth muscle tissue	UBERON:0001135	99.31	gold quality
rectum	UBERON:0001052	99.29	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.29	gold quality
jejunal mucosa	UBERON:0000399	99.27	gold quality
cauda epididymis	UBERON:0004360	99.23	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.22	gold quality
mucosa of transverse colon	UBERON:0004991	99.21	gold quality
endometrium	UBERON:0001295	99.20	gold quality
body of pancreas	UBERON:0001150	99.18	gold quality
pylorus	UBERON:0001166	99.16	gold quality
duodenum	UBERON:0002114	99.14	gold quality
ascending aorta	UBERON:0001496	99.10	gold quality
thoracic aorta	UBERON:0001515	99.10	gold quality
descending thoracic aorta	UBERON:0002345	99.06	gold quality
colonic mucosa	UBERON:0000317	99.05	gold quality
upper lobe of lung	UBERON:0008948	99.05	gold quality
trachea	UBERON:0003126	99.04	gold quality
upper lobe of left lung	UBERON:0008952	99.03	gold quality
right ovary	UBERON:0002118	99.01	gold quality
tendon of biceps brachii	UBERON:0008188	99.01	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	2086.01
E-CURD-122	yes	38.78
E-MTAB-9067	yes	14.93
E-MTAB-10042	yes	11.61
E-GEOD-130148	yes	4.20
E-CURD-97	no	1972.16
E-HCAD-4	no	87.81
E-HCAD-31	no	21.64
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DDIT3, ESR1, SP1

miRNA regulators (miRDB)

71 targeting PDIA3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-7152-3P	99.97	67.47	849
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-1287-3P	99.63	66.93	492
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-3123	99.47	67.15	2693

Literature-anchored findings (GeneRIF, showing 40)

• We found that ERp57 binds to the P-domain of calreticulin, an independently folding domain comprising residues 189-288. (PMID:11842220)
• The oxidoreductase ERp57 efficiently reduces partially folded in preference to fully folded MHC class I molecules. (PMID:12032078)
• Stat3 and GRP58 were observed to be coassociated with cytoplasmic membranes (PMID:12060494)
• Transglutaminase activity of human ER-60 (PMID:12162574)
• role in class I loading process (PMID:12235131)
• Data show that CD1d associates in the ER with both calnexin and calreticulin and with the thiol oxidoreductase ERp57 in a manner dependent on glucose trimming of its N-linked glycans. (PMID:12239218)
• multiple domains are involved in this protein-protein interaction and that the b’ domain of ERp57 cannot be replaced by that of protein disulfide isomerase (PMID:14732712)
• characterized several fundamental structural and functional properties of ERp57, such as domain organization, shape, redox potential, and the ability to catalyze disulfide reduction, disulfide isomerization, and dithiol oxidation in substrate proteins (PMID:14871896)
• propose a model where the region of ERp57 equivalent to the primary substrate binding site of archetypal PDI is occupied by calreticulin and suggest that the ER lectins act as adaptor molecules that define the substrate specificity of ERp57 (PMID:14871899)
• identification of the site of interaction with calnexin and calreticulin; the contribution of both the b and b’ domains to the binding with CNX and CRT was revealed (PMID:15236594)
• ERp57 shares functional properties with protein disulfide isomerase and that both are clearly different from other oxidoreductases (PMID:15328618)
• Considering the functional association of the two proteins, the overexpression of ERp57 observed in a variety of transformed cells might be relevant to the oncogenic properties of STAT3. (PMID:15451439)
• 1,25D3-MARRS protein and vitamin D receptor work together to fine tune intestinal Ca2+ absorption (PMID:15862831)
• Based on immunoblotting studies of cerebrospinal fluid (CSF) from normals, we find that the bulk of the abetas are bound to the ER chaperones, ERp57 and calreticulin. (PMID:15896298)
• ERp57 is detected in neonatal Fc receptor (FcRn)-calnexin complexes, suggesting its role in disulfide bond formation of FcRn heavy chain. (PMID:16002696)
• Tapasin association specifically inhibits the escape pathway required for disulfide-bond isomerization within conventional protein substrates, suggesting a specific structural role for ERp57 within the MHC class I peptide-loading complex. (PMID:16193070)
• analysis of the role of PDI in native disulfide bond formation (PMID:16368681)
• analyzed the cooperation of ER-60 and BiP in the oxidative refolding of denatured proteins (PMID:16428306)
• ERp27 is bound by ERp57 both in vitro and in vivo by a similar mechanism by which ERp57 binds calreticulin (PMID:16940051)
• ERp57 appears to cooperate with Ref-1 in the regulation of gene expression mediated by redox-sensitive transcription factors and in the adaptive response of the cell to oxidative insult. (PMID:16962936)
• We would suggest that at least part of the mechanism of action of ERp57/GRP58 takes place through the regulation of still- unidentified stress-response genes. (PMID:17061245)
• Recruitment of major histocompatibility complex class I molecules into the peptide-loading complex in the endoplasmic reticulum is a structural role for ERp57. (PMID:17150345)
• ERp57 has a role in the isomerisation of non-native disulphide bonds in specific glycoprotein substrates (PMID:17170699)
• loss of ERp57 expression correlated with more aggressive disease and could provide useful prognostic information for gastric cancer patients (PMID:17188166)
• ERp57 is involved in differentiation of certain cancer cells and in muscle function. (PMID:17456022)
• Results show that ERp57 is a component of human sperm acrosome proteins, which play a critical role in gamete fusion. ERp57 could be a novel phenotype marker for male infertility and has the potential to be used to assess sperm selection for IVF. (PMID:17704119)
• Endoplasmic reticulum chaperones stabilize nicotinic receptor subunits and regulate receptor assembly. (PMID:17728248)
• the presence of ERp57 is important for the stability of core loading complexes, and in its absence, the core loading complexes may form stable aggregates within the ER (PMID:17822402)
• Cell stress induced by the parkinsonian mimetic, oxidopamine, is concurrent with oxidation of the chaperone, ERp57, and aggresome formation. (PMID:17848102)
• Valsartan, a selective Ang II type 1 (AT1) receptor blocker, and N-acetylcysteine, an antioxidant, inhibited both of these modifications, indicating the contribution of AT1 receptor and reactive oxygen species to oxidation of Prx2. (PMID:17964282)
• A ternary complex between heavy chain, ERp57, and tapasin was observed and shown to be stabilized by a disulfide between both tapasinheavy chain and tapasin-ERp57. (PMID:18039656)
• the function of ERp57 in peptide loading is likely caused by other ERp57 functional domains or a combinatorial feature of the tapasin-ERp57 conjugate (PMID:18650385)
• ERp57 must be physically associated with the calnexin cycle to catalyze isomerization reactions with most of its substrates (PMID:19054761)
• the 2.6 A resolution structure of the tapasin-ERp57 core of the peptide-loading complex (PMID:19119025)
• Knockdown of ERp57 confers cellular protection against hyperoxia- or tunicamycin-induced apoptosis by inhibition of caspase-3 activation and stimulation of BiP/GRP78 induction. (PMID:19411306)
• tapasin conjugation with ERp57 is as critical as its integration into the membrane for efficient MHC class I assembly, surface expression, and Ag presentation to CD8+ T cells. (PMID:19701894)
• ERp57 plays an important role in chemoresistance mechanisms in ovarian cancer by modulating the attachment of microtubules to chromosomes following paclitaxel treatment through its interaction with TUBB3. (PMID:19714814)
• ERp57 is a necessary cofactor for the regulation of at least a subset of STAT3-dependent genes. (PMID:19995546)
• t\The over expression of protein disulfide isomerase family A led to an gonadotropin releasing hormone receptor retention in plasma membrane. (PMID:20029959)
• genes MAP3K5 and PDIA3 are associated with malignant stages of prostate cancer and therefore provide novel potential biomarkers (PMID:20035634)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdia3	ENSDARG00000102640
mus_musculus	Pdia3	ENSMUSG00000027248
rattus_norvegicus	Pdia3	ENSRNOG00000015018
drosophila_melanogaster	ERp60	FBGN0033663
drosophila_melanogaster	Tmx3	FBGN0036579
drosophila_melanogaster	Pdi	FBGN0286818
caenorhabditis_elegans		WBGENE00003962
caenorhabditis_elegans		WBGENE00003963
caenorhabditis_elegans	pdi-3	WBGENE00003964
caenorhabditis_elegans	M04D5.1	WBGENE00014807
caenorhabditis_elegans	ZK973.11	WBGENE00022836

Paralogs (13): ERP44 (ENSG00000023318), PDIA5 (ENSG00000065485), TMX4 (ENSG00000125827), ERP27 (ENSG00000139055), TMX1 (ENSG00000139921), PDIA6 (ENSG00000143870), TXNDC11 (ENSG00000153066), PDIA4 (ENSG00000155660), TMX3 (ENSG00000166479), PDILT (ENSG00000169340), PDIA2 (ENSG00000185615), P4HB (ENSG00000185624), TXNDC5 (ENSG00000239264)

Protein

Protein identifiers

Protein disulfide-isomerase A3 — P30101 (reviewed: P30101)

Alternative names: 58 kDa glucose-regulated protein, 58 kDa microsomal protein, Disulfide isomerase ER-60, Endoplasmic reticulum resident protein 57, Endoplasmic reticulum resident protein 60

All UniProt accessions (22): P30101, A0A8I5KNU9, A0A8I5KP58, A0A8I5KPY2, A0A8I5KRV3, A0A8I5KS72, A0A8I5KT88, A0A8I5KTA1, A0A8I5KTT8, A0A8I5KW00, A0A8I5KW33, A0A8I5KXC9, A0A8I5KXE2, A0A8I5KYJ6, A0A8I5QJ61, A0A8I5QJM1, A0A8I5QKQ5, A0A8I5QKT6, F8WBS6, F8WBW5, H7BZJ3, V9HVY3

UniProt curated annotations — full annotation on UniProt →

Function. Protein disulfide isomerase that catalyzes the formation, isomerization, and reduction or oxidation of disulfide bonds in client proteins and functions as a protein folding chaperone. Core component of the major histocompatibility complex class I (MHC I) peptide loading complex where it functions as an essential folding chaperone for TAPBP. Through TAPBP, assists the dynamic assembly of the MHC I complex with high affinity antigens in the endoplasmic reticulum. Therefore, plays a crucial role in the presentation of antigens to cytotoxic T cells in adaptive immunity.

Subunit / interactions. Part of the major histocompatibility complex class I (MHC I) peptide loading complex composed of TAP1, TAP2, B2M, MHC heavy chain, TAPBP, PDIA3, and CALR. Interacts with ERP27 and CANX. Interacts with SERPINA2 and with the S and Z variants of SERPINA1. Interacts with ATP2A2.

Subcellular location. Endoplasmic reticulum. Endoplasmic reticulum lumen. Melanosome.

Tissue specificity. Detected in the flagellum and head region of spermatozoa (at protein level). Expressed in liver, stomach and colon (at protein level). Expressed in gastric parietal cells and chief cells (at protein level).

Post-translational modifications. Within the major histocompatibility complex class I (MHC I) peptide loading complex forms reversible disulfide-linked heterodimers with TAPBP as part of its protein folding chaperone activity. This is essential to assist the dynamic assembly of the MHC I complex with high affinity antigens in the endoplasmic reticulum. Phosphorylated.

Activity regulation. Association with calcitriol does not affect its enzymatic activity.

Similarity. Belongs to the protein disulfide isomerase family.

RefSeq proteins (1): NP_005304* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005788	PDI_thioredoxin-like_dom	Domain
IPR005792	Prot_disulphide_isomerase	Family
IPR013766	Thioredoxin_domain	Domain
IPR017937	Thioredoxin_CS	Conserved_site
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR041868	PDIA3_PDI_b	Domain

Pfam: PF00085, PF13848

Enzyme classification (BRENDA):

• EC 5.3.4.1 — protein disulfide-isomerase (BRENDA: 81 organisms, 481 substrates, 347 inhibitors, 35 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CYSTEINE	1–3	3
MYCOTHIOL-COUPLED HYDROXYETHYL DISULFIDE	0.46–33.69	3
RIBONUCLEASE	0.002–0.01	3
RNASE A	0.007–0.05	3
2-MERCAPTOETHANOL	0.2–0.8	2
DITHIOTHREITOL	0.003–0.0054	2
GSH	5–17	2
RNASE	0.028–0.063	2
SCRAMBLED RIBONUCLEASE	0.0011–0.0033	2
DENATURED-REDUCED LYSOZYME	0.0253	1
INSULIN	2.026	1
INSULIN-(SS)	0.005	1
SCRAMBLED REOXIDIZED LYSOZYME	0.0116	1
SCRAMBLED RNASE	0.02	1
SRNASE	—	0

UniProt features (97 total): strand 21, helix 18, turn 11, sequence conflict 9, modified residue 8, mutagenesis site 8, site 6, active site 4, disulfide bond 4, domain 2, signal peptide 1, chain 1, sequence variant 1, region of interest 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
9WQU	X-RAY DIFFRACTION	1.8
2H8L	X-RAY DIFFRACTION	2
3F8U	X-RAY DIFFRACTION	2.6
7QNG	X-RAY DIFFRACTION	2.7
7QPD	ELECTRON MICROSCOPY	3.73
6ENY	ELECTRON MICROSCOPY	5.8
2ALB	SOLUTION NMR
2DMM	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30101-F1	91.57	0.83

Functional residue map

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

Catalytic / active sites (10): 409 (nucleophile); 58 (contributes to redox potential value); 59 (contributes to redox potential value); 119 (lowers pka of c-terminal cys of first active site); 407 (contributes to redox potential value); 408 (contributes to redox potential value); 471 (lowers pka of c-terminal cys of second active site); 57 (nucleophile); 60 (nucleophile); 406 (nucleophile)

Post-translational modifications (8): 61, 129, 152, 218, 252, 319, 362, 494

Disulfide bonds (4): 57–60, 57, 85–92, 406–409

Mutagenesis-validated functional residues (8):

Position	Phenotype
57	no loss of activity. no loss of activity; when associated with a-406.
57	activity changed to serine protease.
60	trapped via disulfide bond with tapbp.
60	activity changed to serine protease; when associated with s-409.
406	no loss of activity. no loss of activity; when associated with a-57.
406	activity changed to serine protease.
409	no effect on disulfide bond with tapbp.
409	activity changed to serine protease; when associated with s-60.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1236974	ER-Phagosome pathway
R-HSA-901042	Calnexin/calreticulin cycle
R-HSA-983170	Antigen Presentation: Folding, assembly and peptide loading of class I MHC
R-HSA-9918432	Maturation of DENV proteins

MSigDB gene sets: 256 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, RNGTGGGC_UNKNOWN, MODULE_93, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_ANTIGEN_PRESENTATION_FOLDING_ASSEMBLY_AND_PEPTIDE_LOADING_OF_CLASS_I_MHC, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_PLATELET_ACTIVATION, GOCC_CELL_SURFACE, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, TGACCTY_ERR1_Q2, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_ANTIGEN, GOBP_WOUND_HEALING, GOBP_CELL_CELL_ADHESION

GO Biological Process (10): adaptive immune response (GO:0002250), peptide antigen assembly with MHC class I protein complex (GO:0002502), protein folding (GO:0006457), protein folding in endoplasmic reticulum (GO:0034975), response to endoplasmic reticulum stress (GO:0034976), platelet aggregation (GO:0070527), extrinsic apoptotic signaling pathway (GO:0097191), cellular response to interleukin-7 (GO:0098761), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), immune system process (GO:0002376)

GO Molecular Function (11): RNA binding (GO:0003723), protein disulfide isomerase activity (GO:0003756), cysteine-type endopeptidase activity (GO:0004197), C-type glycerophospholipase activity (GO:0004629), protein-disulfide reductase activity (GO:0015035), disulfide oxidoreductase activity (GO:0015036), identical protein binding (GO:0042802), protein folding chaperone (GO:0044183), lncRNA binding (GO:0106222), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (12): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), focal adhesion (GO:0005925), cell surface (GO:0009986), melanosome (GO:0042470), MHC class I peptide loading complex (GO:0042824), phagocytic vesicle (GO:0045335), recycling endosome membrane (GO:0055038), Tapasin-ERp57 complex (GO:0061779), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Antigen processing-Cross presentation	1
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1
Class I MHC mediated antigen processing & presentation	1
Dengue Virus Genome Translation and Replication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein folding	2
catalytic activity, acting on a protein	2
intracellular membrane-bounded organelle	2
membrane protein complex	2
endoplasmic reticulum protein-containing complex	2
immune response	1
MHC class I protein complex assembly	1
antigen processing and presentation of peptide antigen via MHC class I	1
peptide antigen assembly with MHC protein complex	1
cellular process	1
protein maturation	1
cellular response to stress	1
platelet activation	1
homotypic cell-cell adhesion	1
cell surface receptor signaling pathway	1
apoptotic signaling pathway	1
cellular response to cytokine stimulus	1
response to interleukin-7	1
extrinsic apoptotic signaling pathway	1
positive regulation of apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway	1
biological_process	1
nucleic acid binding	1
intramolecular oxidoreductase activity, transposing S-S bonds	1
endopeptidase activity	1
cysteine-type peptidase activity	1
glycerophospholipase activity	1
phosphoric diester hydrolase activity	1
disulfide oxidoreductase activity	1
oxidoreductase activity, acting on a sulfur group of donors	1
protein binding	1
molecular_function	1
RNA binding	1
binding	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
endoplasmic reticulum	1
intracellular organelle lumen	1
cell-substrate junction	1

Protein interactions and networks

STRING

3767 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDIA3	CALR	P27797	999
PDIA3	CANX	P27824	998
PDIA3	TAPBP	O15533	997
PDIA3	HSPA5	P11021	986
PDIA3	B2M	P01884	983
PDIA3	ERP27	Q96DN0	945
PDIA3	HSPA8	P11142	844
PDIA3	XBP1	P17861	841
PDIA3	TXN	P10599	836
PDIA3	HSP90AB1	P08238	831
PDIA3	GAPDH	P00354	827
PDIA3	HSP90B1	P14625	826
PDIA3	STIM1	Q13586	826
PDIA3	HYOU1	Q9Y4L1	816
PDIA3	HERPUD1	Q15011	796

IntAct

321 interactions, top by confidence:

A	B	Type	Score
TAP1	TAPBP	psi-mi:“MI:0914”(association)	0.800
APP	CALR	psi-mi:“MI:0914”(association)	0.740
CFTR	PDIA3	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
APP	PDIA3	psi-mi:“MI:0915”(physical association)	0.700
PDIA3	APP	psi-mi:“MI:0915”(physical association)	0.700
CALR	PDIA3	psi-mi:“MI:0915”(physical association)	0.670
TAP1	PDIA3	psi-mi:“MI:0915”(physical association)	0.620
CDC25A	YWHAQ	psi-mi:“MI:2364”(proximity)	0.570
B2M	TAPBP	psi-mi:“MI:0915”(physical association)	0.570
PDIA3	CANX	psi-mi:“MI:0407”(direct interaction)	0.560
CLU	CANX	psi-mi:“MI:0914”(association)	0.530
INHA	HSPA5	psi-mi:“MI:0914”(association)	0.530
COL1A1	GOLIM4	psi-mi:“MI:0914”(association)	0.500

BioGRID (668): PDIA3 (Affinity Capture-MS), PDIA3 (Affinity Capture-MS), PDIA3 (Affinity Capture-MS), PDIA3 (Affinity Capture-MS), PDIA3 (Affinity Capture-MS), PDIA3 (Reconstituted Complex), PDIA3 (Affinity Capture-MS), PDIA3 (Reconstituted Complex), PDIA3 (Affinity Capture-RNA), ATP5O (Co-fractionation), CALR (Co-fractionation), DDX17 (Co-fractionation), FLNA (Co-fractionation), HMBS (Co-fractionation), NMD3 (Co-fractionation)

ESM2 similar proteins: A0A8M1N5Y4, A3KPF5, A8WG88, O22925, O80977, P08003, P11598, P13667, P30040, P30101, P32474, P38659, P52555, P52588, P57759, P81623, P81628, P93026, P93484, Q0E0I1, Q0JD42, Q0WL80, Q17688, Q2KIL5, Q43116, Q498R3, Q56ZQ3, Q5FVM7, Q5I0H9, Q5R5L3, Q5RDG4, Q5WA72, Q66GQ3, Q67IX6, Q6GNG3, Q6NRT6, Q6P5E4, Q7JW12, Q7XRB5, Q8IXB1

Diamond homologs: A0A8M1N5Y4, A3KPF5, D4B2L8, O13704, O13811, O22022, O22263, O48773, O83889, P05307, P07591, P07887, P08003, P09103, P0A4L1, P0A4L2, P0AGG4, P0AGG5, P0AGG6, P0AGG7, P11598, P12243, P12865, P13667, P17967, P21195, P23400, P27773, P30101, P33791, P34329, P37395, P38657, P38658, P38659, P38660, P38661, P46843, P50254, P50338

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
LYN	unknown	PDIA3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 200 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
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	5	20.3×	1e-03
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	6	18.5×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of release of cytochrome c from mitochondria	5	24.5×	1e-03
protein folding	9	5.7×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	58
Likely benign	5
Benign	15

Top pathogenic / likely-pathogenic (0)

SpliceAI

1378 predictions. Top by Δscore:

Variant	Effect	Δscore
15:43746703:CCTGG:C	donor_loss	1.0000
15:43746704:CTG:C	donor_gain	1.0000
15:43746705:TG:T	donor_gain	1.0000
15:43746705:TGG:T	donor_loss	1.0000
15:43746706:GG:G	donor_gain	1.0000
15:43746706:GGT:G	donor_loss	1.0000
15:43746707:G:GG	donor_gain	1.0000
15:43746708:T:A	donor_loss	1.0000
15:43753811:A:AG	acceptor_gain	1.0000
15:43753811:AATAC:A	acceptor_gain	1.0000
15:43753812:A:G	acceptor_gain	1.0000
15:43753814:A:AG	acceptor_gain	1.0000
15:43753814:AC:A	acceptor_gain	1.0000
15:43753815:C:CA	acceptor_gain	1.0000
15:43753815:C:G	acceptor_gain	1.0000
15:43753819:T:G	acceptor_gain	1.0000
15:43753821:TAGG:T	acceptor_loss	1.0000
15:43753822:A:AG	acceptor_gain	1.0000
15:43753823:G:GG	acceptor_gain	1.0000
15:43753823:GGT:G	acceptor_gain	1.0000
15:43753900:AAGG:A	donor_loss	1.0000
15:43753901:AG:A	donor_gain	1.0000
15:43753902:GG:G	donor_gain	1.0000
15:43753902:GGTA:G	donor_loss	1.0000
15:43753903:G:GG	donor_gain	1.0000
15:43753904:TAA:T	donor_loss	1.0000
15:43756643:CTTTA:C	acceptor_loss	1.0000
15:43756644:TTTA:T	acceptor_loss	1.0000
15:43756645:TTAGG:T	acceptor_loss	1.0000
15:43756646:TAGGT:T	acceptor_loss	1.0000

AlphaMissense

3372 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:43746693:T:C	F52L	1.000
15:43746695:C:A	F52L	1.000
15:43746695:C:G	F52L	1.000
15:43746700:C:A	A54D	1.000
15:43753824:G:C	W56C	1.000
15:43753824:G:T	W56C	1.000
15:43753825:T:C	C57R	1.000
15:43753826:G:A	C57Y	1.000
15:43753826:G:T	C57F	1.000
15:43753827:T:G	C57W	1.000
15:43753831:C:G	H59D	1.000
15:43753833:C:A	H59Q	1.000
15:43753833:C:G	H59Q	1.000
15:43753834:T:C	C60R	1.000
15:43753835:G:A	C60Y	1.000
15:43753835:G:T	C60F	1.000
15:43753836:C:G	C60W	1.000
15:43756655:T:C	C85R	1.000
15:43756656:G:A	C85Y	1.000
15:43756656:G:T	C85F	1.000
15:43756657:C:G	C85W	1.000
15:43756677:G:A	C92Y	1.000
15:43756678:T:G	C92W	1.000
15:43756700:T:C	Y100H	1.000
15:43756700:T:G	Y100D	1.000
15:43756701:A:G	Y100C	1.000
15:43756703:C:A	P101T	1.000
15:43756703:C:T	P101S	1.000
15:43756704:C:A	P101Q	1.000
15:43769573:T:C	L398P	1.000

dbSNP variants (sampled 300 via entrez): RS1000111513 (15:43767611 A>C), RS1000264429 (15:43760497 G>A,T), RS1000394505 (15:43767336 G>T), RS1000469571 (15:43760800 T>G), RS1000583427 (15:43766524 A>G), RS1001055581 (15:43757768 A>G), RS1001076645 (15:43771978 T>C), RS1001119725 (15:43768851 G>A,T), RS1001364998 (15:43764193 C>G,T), RS1001617789 (15:43760613 C>A), RS1001675608 (15:43761921 A>T), RS1001783261 (15:43755156 T>C), RS1001969578 (15:43762525 A>T), RS1002110527 (15:43756463 C>G,T), RS1002127528 (15:43748544 G>A)

Disease associations

OMIM: gene MIM:602046 | disease phenotypes: MIM:603720, MIM:611102

GenCC curated gene-disease

Mondo (3): autosomal recessive nonsyndromic hearing loss 16 (MONDO:0011364), deafness-infertility syndrome (MONDO:0012621), intellectual disability (MONDO:0001071)

Orphanet (3): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Deafness-infertility syndrome (Orphanet:94064), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002935_24	Lead levels	9.000000e-06
GCST006585_2247	Blood protein levels	2.000000e-09
GCST010244_18	Triglyceride levels	2.000000e-115
GCST90016666_5	Liver volume	5.000000e-21

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C566339	Deafness, Autosomal Recessive 16 (supp.)
C567010	Deafness, Sensorineural, And Male Infertility (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296001 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 5.-.-.- Isomerases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
punicalagin	Inhibition	5.82	pIC50

ChEMBL bioactivities

9 potent at pChembl≥5 of 12 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.99	Kd	102.8	nM	CHEMBL5653589
6.99	ED50	102.8	nM	CHEMBL5653589
5.82	IC50	1520	nM	CHEMBL6146042
5.62	IC50	2400	nM	JUGLONE
5.52	Kd	3029	nM	CHEMBL3752910
5.52	ED50	3029	nM	CHEMBL3752910
5.49	IC50	3240	nM	CHEMBL5418475
5.32	IC50	4800	nM	CHEMBL4751979
5.16	IC50	6980	nM	CHEMBL5399770

PubChem BioAssay actives

6 with measured affinity, of 20 total; 6 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-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148963: Binding affinity to human PDIA3 incubated for 45 mins by Kinobead based pull down assay	kd	0.1028	uM
5-hydroxynaphthalene-1,4-dione	2034960: Inhibition of human recombinant ERp57 assessed as inhibition of E-GSH formation using Di-E-GSSG as substrate measured for 60 mins in presence of DTT by fluorescence based analysis	ic50	2.4000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148963: Binding affinity to human PDIA3 incubated for 45 mins by Kinobead based pull down assay	kd	3.0294	uM
[(2R,3R,4S,5R,6R)-3,4,5-triacetyloxy-6-(8-hydroxy-1,4-dioxonaphthalen-2-yl)oxyoxan-2-yl]methyl acetate	2034960: Inhibition of human recombinant ERp57 assessed as inhibition of E-GSH formation using Di-E-GSSG as substrate measured for 60 mins in presence of DTT by fluorescence based analysis	ic50	3.2400	uM
(1E)-1-nonylidene-3-(trifluoromethyl)indene-5,6-diol	1687768: Inhibition of PDIA3 (unknown origin) expressed in Escherichia coli BL21 (DE3) incubated for 1 hr and measured by insulin reduction assay	ic50	4.8000	uM
[(2S,3S,4S,5R,6S)-4,5,6-triacetyloxy-2-[(8-hydroxy-1,4-dioxonaphthalen-2-yl)sulfanylmethyl]oxan-3-yl] acetate	2034960: Inhibition of human recombinant ERp57 assessed as inhibition of E-GSH formation using Di-E-GSSG as substrate measured for 60 mins in presence of DTT by fluorescence based analysis	ic50	6.9800	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	5
sodium arsenite	affects expression, affects binding, increases reaction, decreases expression, increases expression	4
bisphenol A	decreases expression, increases expression, affects expression	3
Tobacco Smoke Pollution	increases metabolic processing, affects expression, increases expression	3
Cadmium Chloride	increases abundance, increases expression, decreases expression	3
Resveratrol	affects expression, affects secretion	2
Copper	affects binding	2
Valproic Acid	decreases methylation, increases expression	2
aristolochic acid I	decreases expression, increases expression	1
bisphenol F	increases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
arsenite	increases oxidation	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	increases expression	1
4-hydroxy-2-nonenal	affects binding	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
lead chloride	decreases expression	1
cupric oxide	decreases expression	1
epigallocatechin gallate	increases expression	1
microcystin RR	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CD 437	decreases expression	1
azaspiracid	increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
UCF 101	increases expression	1
quinocetone	increases expression	1
bromovanin	decreases expression	1

ChEMBL screening assays

14 unique, capped per target: 12 binding, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4119040	Binding	Binding affinity to PDIA3 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem
CHEMBL4729813	ADMET	Inhibition of PDIA3 (unknown origin) at 40 uM using bovine insulin as substrate preincubated for 1 hr followed by substrate addition	Characterization of Aminobenzylphenols as Protein Disulfide Isomerase Inhibitors in Glioblastoma Cell Lines. — J Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1Y6	Abcam A-549 PDIA3 KO	Cancer cell line	Male
CVCL_D2CE	Abcam HCT 116 PDIA3 KO	Cancer cell line	Male
CVCL_D2NU	Abcam THP-1 PDIA3 KO	Cancer cell line	Male
CVCL_TC74	HAP1 PDIA3 (-) 1	Cancer cell line	Male
CVCL_XR49	HAP1 PDIA3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders