GLRX3

Summary

GLRX3 (glutaredoxin 3, HGNC:15987) is a protein-coding gene on chromosome 10q26.3, encoding Glutaredoxin-3 (O76003). Together with BOLA2, acts as a cytosolic iron-sulfur (Fe-S) cluster assembly factor that facilitates [2Fe-2S] cluster insertion into a subset of cytosolic proteins. It is a selective cancer dependency (DepMap: 19.0% of cell lines).

This gene encodes a member of the glutaredoxin family. Glutaredoxins are oxidoreductase enzymes that reduce a variety of substrates using glutathione as a cofactor. The encoded protein binds to and modulates the function of protein kinase C theta. The encoded protein may also inhibit apoptosis and play a role in cellular growth, and the expression of this gene may be a marker for cancer. Pseudogenes of this gene are located on the short arm of chromosomes 6 and 9. Alternatively spliced transcript variants have been observed for this gene.

Source: NCBI Gene 10539 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 74 total — 2 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 19.0% of screened cell lines
• MANE Select transcript: NM_006541

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15987
Approved symbol	GLRX3
Name	glutaredoxin 3
Location	10q26.3
Locus type	gene with protein product
Status	Approved
Aliases	PICOT, bA500G10.4, GRX3, GLRX4, GRX4
Ensembl gene	ENSG00000108010
Ensembl biotype	protein_coding
OMIM	612754
Entrez	10539

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 20 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000331244, ENST00000368644, ENST00000481034, ENST00000486974, ENST00000496195, ENST00000619341, ENST00000861471, ENST00000861472, ENST00000861473, ENST00000861474, ENST00000861475, ENST00000916454, ENST00000916455, ENST00000916456, ENST00000916457, ENST00000916458, ENST00000916459, ENST00000948445, ENST00000948446, ENST00000948447, ENST00000948448, ENST00000948449, ENST00000948450, ENST00000948451

RefSeq mRNA: 3 — MANE Select: NM_006541 NM_001199868, NM_001321980, NM_006541

CCDS: CCDS7661

Canonical transcript exons

ENST00000331244 — 11 exons

Exon	Start	End
ENSE00000577957	130174997	130175089
ENSE00000728668	130145211	130145319
ENSE00000728676	130160796	130160997
ENSE00000728678	130166507	130166679
ENSE00000728681	130166919	130166980
ENSE00000728683	130169433	130169490
ENSE00000728687	130171584	130171636
ENSE00000728691	130174867	130174906
ENSE00001447656	130179342	130179672
ENSE00003477570	130159995	130160069
ENSE00003844661	130136391	130136512

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 96.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 74.2244 / max 443.1959, expressed in 1825 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107681	74.1873	1825
206054	0.0371	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.59	gold quality
islet of Langerhans	UBERON:0000006	96.40	gold quality
adrenal tissue	UBERON:0018303	96.33	gold quality
right testis	UBERON:0004534	96.23	gold quality
left testis	UBERON:0004533	96.03	gold quality
esophagus mucosa	UBERON:0002469	95.91	gold quality
right adrenal gland	UBERON:0001233	95.77	gold quality
right adrenal gland cortex	UBERON:0035827	95.72	gold quality
left adrenal gland	UBERON:0001234	95.60	gold quality
lower esophagus mucosa	UBERON:0035834	95.51	gold quality
left adrenal gland cortex	UBERON:0035825	95.37	gold quality
testis	UBERON:0000473	95.35	gold quality
esophagus	UBERON:0001043	95.23	gold quality
body of pancreas	UBERON:0001150	95.21	gold quality
adrenal gland	UBERON:0002369	95.21	gold quality
heart left ventricle	UBERON:0002084	95.05	gold quality
rectum	UBERON:0001052	95.04	gold quality
heart right ventricle	UBERON:0002080	95.03	gold quality
ganglionic eminence	UBERON:0004023	95.02	gold quality
smooth muscle tissue	UBERON:0001135	95.01	gold quality
cardiac ventricle	UBERON:0002082	94.97	gold quality
pancreas	UBERON:0001264	94.88	gold quality
skin of abdomen	UBERON:0001416	94.85	gold quality
ventricular zone	UBERON:0003053	94.85	gold quality
ectocervix	UBERON:0012249	94.76	gold quality
cartilage tissue	UBERON:0002418	94.73	gold quality
adrenal cortex	UBERON:0001235	94.70	gold quality
right atrium auricular region	UBERON:0006631	94.61	gold quality
skin of leg	UBERON:0001511	94.60	gold quality
cortical plate	UBERON:0005343	94.60	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-93593	no	7.05
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

37 targeting GLRX3, 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-429	100.00	73.44	2698
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-4999-5P	99.35	69.15	926
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-6769B-5P	98.73	64.91	1092

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 19.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• dS6K activity is dependent on the Drosophila homologue of the phosphoinositide-dependent protein kinase 1, dPDK1, demonstrating that both dPDK1, as well as dTOR, mediated dS6K activation is phosphatidylinositide-3,4,5-trisphosphate (PIP3)-independent. (PMID:11862217)
• Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. (PMID:12766775)
• S6K activity becomes resistant to amino acid starvation upon loss of Tsc1 and Tsc2 or ectopic activation of Rheb. (PMID:12771962)
• S6 kinase (dS6K) and a single 4E-BP (d4E-BP) are phosphorylated via the insulin and target of rapamycin (TOR) signaling pathways. (PMID:14645523)
• Reaults show that S6K is required for increased Rheb-TOR signaling to sensitize the whole organism to oxidative stress and promote the senescence of locomotor activity. (PMID:17038544)
• ATG1 is a negative regulator of the target of rapamycin (TOR)/S6 kinase (S6K) pathway. (PMID:17347671)
• Results indicate that PP2A, but not other members of this subfamily, is likely to be a major S6K phosphatase in intact cells and is consistent with an important role for this phosphatase in the TOR pathway. (PMID:17570358)
• DHR3 modulates dS6 kinase-dependent growth in Drosophila. (PMID:20463884)
• Data show that female Drosophila melanogaster undergo a dietary switch following mating and that S6 kinase and serotonin production are involved in this switch. (PMID:20471266)
• Data show that mating status modulates food choice in females, that it relies on the action of the sex peptide receptor in sensory neurons, and that neuronal TOR/S6K function affects this decision, possibly signaling the fly’s current nutritional status. (PMID:20471268)
• the effect of allelic variation at S6k on a range of phenotypes associated with metabolism and fitness in an age-, diet-, and sex-specific manner (PMID:20491566)
• S6 kinase localizes to the presynaptic active zone and functions with PDK1 to control synapse development (PMID:21930778)
• our results indicate that S6K1 has an inhibitory effect on autophagic activity under normal nutritional conditions (PMID:23532117)
• MYC and S6K cooperate through coordinate activation of the essential Pol I transcription initiation factor TIF-1A. (PMID:26215099)
• This study showed that p70 S6 kinase (S6k), acting downstream of the insulin receptor (InR) and the small GTPase Arf6, is a key mediator of ethanol-induced sedation in Drosophila (PMID:26586826)
• Findings indicate that Archipelago (Ago)/FBXW7 controls S6kinase (dS6K) protein levels, but do not impinge on the transcript level. (PMID:30656413)
• mTOR-S6K1 pathway mediates cytoophidium assembly (PMID:30857853)
• Identification of PP2A and S6 Kinase as Modifiers of Leucine-Rich Repeat Kinase-Induced Neurotoxicity. (PMID:31664682)
• The S6k/4E-BP mediated growth promoting sub-pathway of insulin signalling cascade is essential to restrict pathogenesis of poly(Q) disorders in Drosophila. (PMID:33744321)
• Glutamine stimulates the S6K/4E-BP branch of insulin signalling pathway to mitigate human poly(Q) disorders in Drosophila disease models. (PMID:37658796)
• Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system. (PMID:38413780)
• thioredoxin-like 2 may have a role in colorectal cancer, as it is the antigen for the monoclonal antibody MC3 specific to colorectal cancer (PMID:18528843)
• Western blot analysis revealed consistent and preferential expression of Glrx3 in lung and colon cancers; results suggest that Glrx3 could take a pivotal role in colon and lung cancer cells during tumorigenesis (PMID:19797004)
• The present results show a direct correlation between PICOT expression levels and increased cell growth, both in vitro and in vivo. (PMID:20170406)
• redox-induced dissociation of the Grx3/PICOT holo complex may be a mechanism of Grx3/PICOT activation in response to reactive oxygen and nitrogen species. (PMID:20226171)
• Demonstrated a differential expression of PICOT in various cell types, with a predominant cytosolic staining of epithelial cells and low or undetectable levels of PICOT in the stroma. (PMID:20498481)
• analysis of primary breast cancer samples demonstrated that enhanced TXNL2 expression correlated with metastasis to the lung and brain and with decreased overall patient survival (PMID:21123948)
• investigations into role of Grx3: Grx3-knockdown in HeLa cells leads to significant delay in mitotic exit and a higher percentage of binucleated cells. (PMID:21575136)
• the unusual [2Fe-2S]-bridging Grx-BolA interaction is conserved in higher eukaryotes and may play a role in signaling cellular iron status in humans. (PMID:22309771)
• these data raise the possibility that the pro-apoptotic role of PICOT is actively regulated via caspase-3-mediated cleavage. (PMID:23415866)
• Data indicate that silencing of Grx3 in HeLa cells decreases the activities of several cytosolic Fe/S proteins, including iron-regulatory protein 1, a major component of posttranscriptional iron regulation. (PMID:23615448)
• findings provide novel insights into the regulation of Grx3, which is crucial for cell survival against environmental insults (PMID:25975981)
• These in vitro studies suggest that human GLRX3 is important for cytosolic Fe-S protein maturation. (PMID:26296460)
• These findings provide an advanced view of the functional role of glutaredoxin-3 in iron metabolism. (PMID:26302480)
• apo GRX3 and apo BOLA2 form a heterotrimeric complex, composed by two BOLA2 molecules and one GRX3 molecule (PMID:26613676)
• GLRX3 might be an oncoprotein in nasopharyngeal carcinoma (PMID:27203742)
• The Glrx3.BolA is a [2Fe-2S] chaperone complex capable of transferring [2Fe-2S] clusters to apoproteins in human cells. (PMID:27519415)
• The findings suggested the vital roles of GLRX3 in OSCC progression through its relationship with EMT progression, and these data also suggest that a strategy of blocking ROS to enhance the activity of GLRX3 knockdown warrants further attention in the treatment of OSCC. (PMID:29397791)
• PICOT knock-down in Jurkat T cells resulted in a reduced histone H3 lysine 27 trimethylation (H3K27me3) at the PRC2 target gene, myelin transcription factor 1 (MYT1), suggesting that PICOT binding to EED alters PRC2-regulated transcriptional repression, and potentially contributes to the epigenetic regulation of chromatin silencing and remodeling. (PMID:30595380)
• PICOT (GLRX3) is a positive regulator of stress-induced DNA-damage response. (PMID:31176019)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	glrx3	ENSDARG00000098785
mus_musculus	Glrx3	ENSMUSG00000031068
rattus_norvegicus	Glrx3	ENSRNOG00000016227
drosophila_melanogaster	Grx3	FBGN0032509
caenorhabditis_elegans		WBGENE00017062

Paralogs (1): GLRX5 (ENSG00000182512)

Protein

Protein identifiers

Glutaredoxin-3 — O76003 (reviewed: O76003)

Alternative names: PKC-interacting cousin of thioredoxin, PKC-theta-interacting protein, Thioredoxin-like protein 2

All UniProt accessions (2): O76003, A0A140VJK1

UniProt curated annotations — full annotation on UniProt →

Function. Together with BOLA2, acts as a cytosolic iron-sulfur (Fe-S) cluster assembly factor that facilitates [2Fe-2S] cluster insertion into a subset of cytosolic proteins. Acts as a critical negative regulator of cardiac hypertrophy and a positive inotropic regulator. Required for hemoglobin maturation. Does not possess any thyoredoxin activity since it lacks the conserved motif that is essential for catalytic activity.

Subunit / interactions. Homodimer; the homodimer is independent of 2Fe-2S clusters. Heterotrimer; forms a heterotrimeric complex composed by two BOLA2 molecules and one GLRX3 molecule; linked by [2Fe-2S] clusters. Interacts (via N-terminus) with PRKCQ/PKC-theta. Interacts (via C-terminus) with CSRP3. Interacts with CSRP2.

Subcellular location. Cytoplasm. Cytosol. Cell cortex. Myofibril. Sarcomere. Z line.

Tissue specificity. Expressed in heart, spleen, testis and, to a lower extent, in thymus and peripheral blood leukocytes. Weakly expressed in lung, placenta, colon and small intestine.

Domain organisation. The thioredoxin domain lacks the two redox-active cysteines. This strongly suggests that it lacks thioredoxin activity.

Miscellaneous. Silencing of Grx3 in HeLa cells decreases the activities of several cytosolic Fe/S proteins, such as ACO1, a major component of post-transcriptional iron regulation. As a consequence, Grx3-depleted cells show decreased levels of ferritin and increased levels of transferrin receptor, features characteristic of cellular iron starvation.

RefSeq proteins (3): NP_001186797, NP_001308909, NP_006532* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002109	Glutaredoxin	Domain
IPR004480	Monothiol_GRX-rel	Family
IPR013766	Thioredoxin_domain	Domain
IPR033658	GRX_PICOT-like	Domain
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF00085, PF00462

UniProt features (52 total): helix 16, strand 15, mutagenesis site 4, sequence conflict 3, domain 3, modified residue 3, sequence variant 2, turn 2, binding site 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2WZ9	X-RAY DIFFRACTION	1.55
3ZYW	X-RAY DIFFRACTION	1.84
2YAN	X-RAY DIFFRACTION	1.9
2DIY	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O76003-F1	89.36	0.72

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 (2): 159; 261

Post-translational modifications (3): 2, 117, 120

Mutagenesis-validated functional residues (4):

Position	Phenotype
159	loss of 2fe-2s-binding; when associated with s-261. loss of 2fe-2s-binding and interaction with bola2; when associated w
197–198	loss of 2fe-2s-binding and interaction with bola2; when associated with s-159.
261	loss of 2fe-2s-binding; when associated with s-159. loss of 2fe-2s-binding and interaction with bola2; when associated w
299–300	loss of 2fe-2s-binding and interaction with bola2; when associated with s-261.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-917937	Iron uptake and transport

MSigDB gene sets: 156 (showing top): TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_CIRCULATORY_SYSTEM_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_CELL_REDOX_HOMEOSTASIS, GOBP_REGULATION_OF_THE_FORCE_OF_HEART_CONTRACTION, GOBP_MUSCLE_ADAPTATION, MODULE_99, GOBP_REGULATION_OF_MUSCLE_HYPERTROPHY, GOBP_REGULATION_OF_SYSTEM_PROCESS, WANG_TARGETS_OF_MLL_CBP_FUSION_DN

GO Biological Process (6): regulation of the force of heart contraction (GO:0002026), intracellular iron ion homeostasis (GO:0006879), negative regulation of cardiac muscle hypertrophy (GO:0010614), iron-sulfur cluster assembly (GO:0016226), [2Fe-2S] cluster assembly (GO:0044571), cell redox homeostasis (GO:0045454)

GO Molecular Function (6): RNA binding (GO:0003723), protein kinase C binding (GO:0005080), identical protein binding (GO:0042802), metal ion binding (GO:0046872), iron-sulfur cluster binding (GO:0051536), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), cell cortex (GO:0005938), Z disc (GO:0030018), dendrite (GO:0030425), iron-sulfur cluster assembly complex (GO:1990229)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	3
regulation of heart contraction	1
regulation of biological quality	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
negative regulation of muscle hypertrophy	1
metallo-sulfur cluster assembly	1
iron-sulfur cluster assembly	1
cellular homeostasis	1
nucleic acid binding	1
protein kinase binding	1
protein binding	1
cation binding	1
metal cluster binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cell periphery	1
I band	1
neuron projection	1
dendritic tree	1
protein-containing complex	1

Protein interactions and networks

STRING

2400 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLRX3	BOLA2	Q9H3K6	943
GLRX3	PRKCQ	Q04759	893
GLRX3	GLRX	P35754	859
GLRX3	CSRP3	P50461	848
GLRX3	GLRX2	Q9NS18	844
GLRX3	CIAPIN1	Q6FI81	807
GLRX3	FOSL2	P15408	804
GLRX3	ISCA1	Q9BUE6	743
GLRX3	BOLA1	Q9Y3E2	734
GLRX3	NFU1	Q9UMS0	733
GLRX3	ISCU	Q9H1K1	713
GLRX3	TYW1	Q9NV66	693
GLRX3	NFS1	Q9Y697	690
GLRX3	ISCA2	Q86U28	679
GLRX3	NUBP1	P53384	674
GLRX3	BOLA3	Q53S33	674

IntAct

517 interactions, top by confidence:

A	B	Type	Score
CIAPIN1	GLRX3	psi-mi:“MI:0915”(physical association)	0.960
GLRX3	CIAPIN1	psi-mi:“MI:0915”(physical association)	0.960
GLRX3	GRN	psi-mi:“MI:0915”(physical association)	0.870
GLRX3	BOLA1	psi-mi:“MI:0915”(physical association)	0.870
BOLA1	GLRX3	psi-mi:“MI:0915”(physical association)	0.870
GRN	GLRX3	psi-mi:“MI:0915”(physical association)	0.870
GLRX3	RGS20	psi-mi:“MI:0915”(physical association)	0.810
RGS20	GLRX3	psi-mi:“MI:0915”(physical association)	0.810
KRTAP4-12	GLRX3	psi-mi:“MI:0915”(physical association)	0.780
GLRX3	KRTAP5-6	psi-mi:“MI:0915”(physical association)	0.780
GLRX3	MOXD1	psi-mi:“MI:0915”(physical association)	0.780
GLRX3	KRTAP4-12	psi-mi:“MI:0915”(physical association)	0.780
KRTAP5-6	GLRX3	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (270): GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid), GLRX3 (Two-hybrid)

ESM2 similar proteins: A1A4Q2, A6NEY8, B2RZ27, E9QI36, O06465, O75131, O76003, O81187, P0A155, P0A156, P12081, P19480, P35340, P55143, Q28EX9, Q28ID3, Q2KI84, Q2KJD7, Q3ZCL8, Q4I963, Q58DA7, Q5FWT7, Q5R4C4, Q5R4R2, Q5RAE1, Q5RC61, Q5XJ54, Q5ZJJ8, Q61035, Q641F1, Q6DBT3, Q6DI37, Q7KLV9, Q80T18, Q80Y14, Q86SX6, Q8BGR9, Q8CI33, Q8K3X2, Q8WVY7

Diamond homologs: B7ZFT1, O05957, O23420, O30824, O74790, O76003, P0AC62, P0AC63, P0AC64, P0AC69, P0AC70, P0AC71, P0AC72, P32642, P35754, P45085, P51384, P57284, P73056, Q02784, Q03835, Q0IWL9, Q0JM76, Q0JQ97, Q19297, Q1RHJ0, Q1XDA3, Q28ID3, Q2QX01, Q48833, Q4QLD2, Q4UK94, Q54EX7, Q555C8, Q58DA7, Q5XJ54, Q68W05, Q68XG4, Q6PBM1, Q6YFE4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GLRX3	“form complex”	“BOLA2-GLRX3 iron-sulfur cluster assembly complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 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
Keratinization	14	20.5×	1e-13

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	47
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1047895	GRCh37/hg19 10q26.2-26.3(chr10:129483682-135434178)	Pathogenic
1706486	GRCh37/hg19 10q26.2-26.3(chr10:129605105-135427143)x1	Pathogenic

SpliceAI

2578 predictions. Top by Δscore:

Variant	Effect	Δscore
10:130136508:GCCAA:G	donor_gain	1.0000
10:130136513:G:GG	donor_gain	1.0000
10:130145317:AAG:A	donor_gain	1.0000
10:130159991:A:AG	acceptor_gain	1.0000
10:130160794:A:AG	acceptor_gain	1.0000
10:130160795:G:GG	acceptor_gain	1.0000
10:130160795:GA:G	acceptor_gain	1.0000
10:130160795:GAA:G	acceptor_gain	1.0000
10:130160795:GAATT:G	acceptor_gain	1.0000
10:130160995:GTG:G	donor_gain	1.0000
10:130160996:TGGTA:T	donor_loss	1.0000
10:130160998:G:GG	donor_gain	1.0000
10:130160999:T:G	donor_loss	1.0000
10:130166502:TACA:T	acceptor_loss	1.0000
10:130166504:CA:C	acceptor_loss	1.0000
10:130166505:A:AT	acceptor_loss	1.0000
10:130166506:G:GC	acceptor_loss	1.0000
10:130166675:TTAAG:T	donor_loss	1.0000
10:130166676:TAAGG:T	donor_loss	1.0000
10:130166677:AAGGT:A	donor_loss	1.0000
10:130166678:AGG:A	donor_loss	1.0000
10:130166679:GGT:G	donor_loss	1.0000
10:130174865:A:AG	acceptor_gain	1.0000
10:130174866:G:GG	acceptor_gain	1.0000
10:130174866:GT:G	acceptor_gain	1.0000
10:130174866:GTGTT:G	acceptor_gain	1.0000
10:130174904:GAA:G	donor_gain	1.0000
10:130174905:AAGTA:A	donor_loss	1.0000
10:130174907:G:GG	donor_gain	1.0000
10:130174908:TAAG:T	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000010287 (10:130134554 C>T), RS1000017786 (10:130137073 G>T), RS1000107260 (10:130171703 C>A,T), RS1000163844 (10:130155141 A>C,G), RS1000164874 (10:130163438 C>T), RS1000173338 (10:130170092 A>G), RS1000256912 (10:130165763 A>G), RS1000309284 (10:130166114 T>A,C), RS1000351167 (10:130159408 A>G), RS1000382470 (10:130138492 A>G), RS1000508449 (10:130156425 G>C), RS1000557801 (10:130171999 C>T), RS1000645069 (10:130167571 G>A), RS1000763746 (10:130161264 C>G), RS1000817480 (10:130154793 C>A,G)

Disease associations

OMIM: gene MIM:612754 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000918_3	HIV-1 susceptibility	7.000000e-06
GCST002938_30	Copper levels	5.000000e-06
GCST003121_15	Alcohol dependence	9.000000e-06
GCST004735_36	Epstein-Barr virus copy number in lymphoblastoid cell lines	8.000000e-06
GCST009172_3	Response to (pegylated) interferon in HBeAg-negative hepatitis B	3.000000e-06
GCST009363_57	Triglyceride levels x short total sleep time interaction (2df test)	3.000000e-09
GCST009369_2	Triglyceride levels x short total sleep time interaction (1df test)	6.000000e-06
GCST011973_3	Colorectal cancer	2.000000e-06
GCST012036_4	Sleep end time	4.000000e-08
GCST90002392_553	Mean corpuscular volume	4.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0007859	response to interferon
EFO:0004530	triglyceride measurement
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066467 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.94	Kd	115.8	nM	CHEMBL5653589
6.94	ED50	115.8	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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	2148435: Binding affinity to human GLRX3 incubated for 45 mins by Kinobead based pull down assay	kd	0.1158	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
bisphenol A	affects expression, decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
bisphenol F	increases expression	1
2,4,6-tribromophenol	increases expression	1
glycidyl methacrylate	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
decabromobiphenyl ether	increases expression	1
arsenite	affects binding, increases reaction	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
frenolicin B	affects binding, decreases activity, decreases abundance, increases abundance, decreases phosphorylation (+1 more)	1
tetrabromobisphenol A	increases expression	1
ochratoxin A	increases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Irinotecan	affects expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	decreases expression	1
Arsenic Trioxide	increases expression	1
Vorinostat	increases expression	1
Benztropine	increases expression	1
Cadmium	increases abundance, increases expression	1
Clozapine	increases expression	1
Diazinon	increases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651477	Binding	Binding affinity to human GLRX3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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