Glutaredoxin-3 (GLRX3)
The protein contains 335 amino acids for an estimated molecular weight of 37432 Da.
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 (PubMed:26613676, PubMed:27519415). Acts as a critical negative regulator of cardiac hypertrophy and a positive inotropic regulator (By similarity). Required for hemoglobin maturation (PubMed:23615448). Does not possess any thyoredoxin activity since it lacks the conserved motif that is essential for catalytic activity. (updated: Jan. 31, 2018)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs13991 | |
| dbSNP:rs2274217 |
The reference OMIM entry for this protein is 612754
Glutaredoxin 3; glrx3
Grx3
Protein kinase c-interacting cousin of thioredoxin; picot
DESCRIPTION
GLRX3 belongs to the monothiol glutaredoxin (GRX) family, members of which are characterized by a cys-gly-phe-ser active-site motif. Most monothiol GRXs bind 2Fe-2S clusters that are coordinated by 2 protein monomers and 2 glutathione molecules. GLRX3 is involved in cellular iron metabolism and participates in various cell signaling pathways (summary by Haunhorst et al., 2013).CLONING
Using protein kinase C (PKC)-theta (PRKCQ, 600448) as bait in a yeast 2-hybrid screen of a Jurkat T-lymphoma cDNA library, Witte et al. (2000) cloned GLRX3, which they designated PICOT. The deduced 335-amino acid protein has a calculated molecular mass of 37.5 kD. It has an N-terminal thioredoxin (TXN; 187700) homology domain followed by tandem repeats of an 84-amino acid PICOT domain. Human PICOT shares 99% amino acid identity with the rat and mouse orthologs. The PICOT domain is highly conserved, and tandem PICOT domains are present in mouse and rat Picot. However, only a single PICOT domain is present in nematodes, yeast, bacteria, viruses, and plants. Northern blot analysis detected a 1.5-kb PICOT transcript in Jurkat cells. RT-PCR detected abundant PICOT expression in heart, spleen, and testis, with lower expression in other tissues. Western blot analysis detected PICOT at an apparent molecular mass of 38 kD. Fractionation of Jurkat cells revealed PICOT in the cytosolic compartment, with very low amounts in the membrane fraction.MAPPING
Hartz (2009) mapped the GLRX3 gene to chromosome 10q26.3 based on an alignment of the GLRX3 sequence (GenBank GENBANK AJ010841) with the genomic sequence (build 36.1),GENE FUNCTION
Using cotransfection and immunoprecipitation analysis with Jurkat cells, Witte et al. (2000) showed that PICOT interacted with PKC-theta and, more weakly, with PKC-zeta (PRKCZ; 176982), but not with PKC-alpha (PRKCA; 176960). Mutation analysis showed that the thioredoxin homology domain of PICOT was required for the interaction. Transfection of PICOT in Jurkat cells reduced basal JNK (see MAPK8; 601158) activity and significantly reduced PKC-theta-induced JNK activation. PICOT also inhibited the transcription factors AP1 (see 165160) and NF-kappa-B (see 164011). Jeong et al. (2008) stated that Picot inhibits pressure overload-induced cardiac hypertrophy in rodents, concomitant with increased ventricular function and cardiomyocyte contractility. They showed that Picot colocalized with Mlp (CSRP3; 600824), which anchors calcineurin (see PPP3CA, 114105) to the Z disc in the sarcomere and is critical for calcineurin-Nfat (see NFATC1; 600489) signaling. The C-terminal half of Picot inhibited cardiac hypertrophy, largely by disrupting the Mlp-calcineurin interaction and thereby negatively regulating calcineurin-Nfat signaling. Haunhorst et al. (2013) found that knockdown of GLRX3 in HeLa cells via small interfering RNA had little effect on mitochondrial iron-dependent proteins but significantly reduced the content and activity of the cytosolic Fe/S proteins IRP1 (ACO1; 100880) and GPAT (PPAT; 172450). These reductions appeared to be due to failure of Fe/S cluster assembly and insertion into the nascent protein. IRP1 showed enhanced ability to bind the iron response element (IRE) of ferritin (see 134790) following GLRX3 knockdown. GLRX3 knockdown was associated with increased expression of transferrin receptor (TFRC; 190010) and decreased expression of ferritin (see FTL, 134790), suggesting ... More on the omim web site
May 12, 2019: Protein entry updated
Automatic update: model status changed
Nov. 17, 2018: Protein entry updated
Automatic update: model status changed
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 612754 was added.
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed