ID   GLRX3_MOUSE             Reviewed;         337 AA.
AC   Q9CQM9; Q5I0V8; Q9JLZ2;
DT   26-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2001, sequence version 1.
DT   27-MAR-2024, entry version 180.
DE   RecName: Full=Glutaredoxin-3;
DE   AltName: Full=PKC-interacting cousin of thioredoxin;
DE            Short=PICOT;
DE   AltName: Full=PKC-theta-interacting protein;
DE            Short=PKCq-interacting protein;
DE   AltName: Full=Thioredoxin-like protein 2;
GN   Name=Glrx3; Synonyms=Picot, Txnl2;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Embryo;
RX   PubMed=10636891; DOI=10.1074/jbc.275.3.1902;
RA   Witte S., Villalba M., Bi K., Liu Y., Isakov N., Altman A.;
RT   "Inhibition of the c-Jun N-terminal kinase/AP-1 and NF-kappaB pathways by
RT   PICOT, a novel protein kinase C-interacting protein with a thioredoxin
RT   homology domain.";
RL   J. Biol. Chem. 275:1902-1909(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Embryonic stem cell, and Head;
RX   PubMed=16141072; DOI=10.1126/science.1112014;
RA   Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA   Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA   Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA   Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA   Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA   Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA   Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA   Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA   Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA   Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA   Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA   Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA   Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA   Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA   Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA   Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA   Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA   Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA   Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA   Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA   Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA   Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA   Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA   Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA   Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA   van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA   Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA   Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA   Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA   Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA   Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA   Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA   Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA   Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT   "The transcriptional landscape of the mammalian genome.";
RL   Science 309:1559-1563(2005).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=Czech II; TISSUE=Kidney, and Mammary tumor;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   PROTEIN SEQUENCE OF 82-94.
RC   TISSUE=Brain;
RA   Lubec G., Yang J.W., Zigmond M.;
RL   Submitted (JUL-2007) to UniProtKB.
RN   [5]
RP   FUNCTION, AND OVEREXPRESSION.
RX   PubMed=16809552; DOI=10.1161/01.res.0000234780.06115.2c;
RA   Jeong D., Cha H., Kim E., Kang M., Yang D.K., Kim J.M., Yoon P.O., Oh J.G.,
RA   Bernecker O.Y., Sakata S., Le T.T., Cui L., Lee Y.H., Kim do H., Woo S.H.,
RA   Liao R., Hajjar R.J., Park W.J.;
RT   "PICOT inhibits cardiac hypertrophy and enhances ventricular function and
RT   cardiomyocyte contractility.";
RL   Circ. Res. 99:307-314(2006).
RN   [6]
RP   FUNCTION, SUBCELLULAR LOCATION, OVEREXPRESSION, AND INTERACTION WITH CSRP2
RP   AND CSRP3.
RX   PubMed=18258855; DOI=10.1161/circresaha.107.165985;
RA   Jeong D., Kim J.M., Cha H., Oh J.G., Park J., Yun S.H., Ju E.S., Jeon E.S.,
RA   Hajjar R.J., Park W.J.;
RT   "PICOT attenuates cardiac hypertrophy by disrupting calcineurin-NFAT
RT   signaling.";
RL   Circ. Res. 102:711-719(2008).
RN   [7]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=18929570; DOI=10.1016/j.yjmcc.2008.09.124;
RA   Cha H., Kim J.M., Oh J.G., Jeong M.H., Park C.S., Park J., Jeong H.J.,
RA   Park B.K., Lee Y.-H., Jeong D., Yang D.K., Bernecker O.Y., Kim do H.,
RA   Hajjar R.J., Park W.J.;
RT   "PICOT is a critical regulator of cardiac hypertrophy and cardiomyocyte
RT   contractility.";
RL   J. Mol. Cell. Cardiol. 45:796-803(2008).
RN   [8]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung,
RC   Pancreas, Spleen, and Testis;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
RN   [9]
RP   STRUCTURE BY NMR OF 241-336.
RG   RIKEN structural genomics initiative (RSGI);
RT   "Solution structure of the picot homology 2 domain of the mouse pkc-
RT   interacting cousin of thioredoxin protein.";
RL   Submitted (NOV-2004) to the PDB data bank.
CC   -!- FUNCTION: Together with BOLA2, acts as a cytosolic iron-sulfur (Fe-S)
CC       cluster assembly factor that facilitates [2Fe-2S] cluster insertion
CC       into a subset of cytosolic proteins (By similarity). Acts as a critical
CC       negative regulator of cardiac hypertrophy and a positive inotropic
CC       regulator (PubMed:16809552, PubMed:18258855, PubMed:18929570). Required
CC       for hemoglobin maturation. Does not possess any thyoredoxin activity
CC       since it lacks the conserved motif that is essential for catalytic
CC       activity (By similarity). {ECO:0000250|UniProtKB:O76003,
CC       ECO:0000269|PubMed:16809552, ECO:0000269|PubMed:18258855,
CC       ECO:0000269|PubMed:18929570}.
CC   -!- SUBUNIT: Homodimer; the homodimer is independent of 2Fe-2S clusters.
CC       Heterotrimer; forms a heterotrimeric complex composed by two BOLA2
CC       molecules and one GLRX3 molecule; linked by [2Fe-2S] clusters.
CC       Interacts (via N-terminus) with PRKCQ/PKC-theta (By similarity).
CC       Interacts (via C-terminus) with CSRP3 (PubMed:18258855). Interacts with
CC       CSRP2 (PubMed:18258855). {ECO:0000250|UniProtKB:O76003,
CC       ECO:0000269|PubMed:18258855}.
CC   -!- INTERACTION:
CC       Q9CQM9; Q8WTY4: Ciapin1; NbExp=4; IntAct=EBI-4319195, EBI-2943068;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC       {ECO:0000250|UniProtKB:O76003}. Cytoplasm, cell cortex
CC       {ECO:0000269|PubMed:18258855}. Cytoplasm, myofibril, sarcomere, Z line
CC       {ECO:0000269|PubMed:18258855}. Note=Under the plasma membrane
CC       (PubMed:18258855). After PMA stimulation, GLRX3 and PRKCQ/PKC-theta
CC       translocate to a more extended submembrane area (PubMed:18258855). In
CC       the Z line, found associated with CSRP3 (PubMed:18258855).
CC       {ECO:0000269|PubMed:18258855}.
CC   -!- DOMAIN: The thioredoxin domain lacks the two redox-active cysteines.
CC       This strongly suggests that it lacks thioredoxin activity.
CC       {ECO:0000305}.
CC   -!- DISRUPTION PHENOTYPE: Homozygous null mutants die in utero some time
CC       between 12.5 and 14.5 dpc. 12.5 dpc embryos have a smaller body size
CC       and hemorrhage in the head. Heterozygous mutants are fertile and show
CC       no abnormalities in growth and development, cardiomyocytes exhibit
CC       significantly reduced contractility. {ECO:0000269|PubMed:18929570}.
CC   -!- MISCELLANEOUS: Transgenic mice with cardiac-specific Glrx3
CC       overexpression show that it is a potent inhibitor of cardiac
CC       hypertrophy induced by pressure overload (transverse aortic
CC       constriction). In addition, overexpression dramatically increases the
CC       ventricular function and cardiomyocyte contractility.
CC       {ECO:0000269|PubMed:16809552, ECO:0000269|PubMed:18258855,
CC       ECO:0000269|PubMed:18929570}.
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DR   EMBL; AF118650; AAF28842.1; -; mRNA.
DR   EMBL; AK010354; BAB26874.1; -; mRNA.
DR   EMBL; AK017371; BAB30712.1; -; mRNA.
DR   EMBL; AK147158; BAE27724.1; -; mRNA.
DR   EMBL; AK152446; BAE31225.1; -; mRNA.
DR   EMBL; AK152634; BAE31376.1; -; mRNA.
DR   EMBL; AK155190; BAE33105.1; -; mRNA.
DR   EMBL; AK167672; BAE39721.1; -; mRNA.
DR   EMBL; BC033506; AAH33506.1; -; mRNA.
DR   EMBL; BC087885; AAH87885.1; -; mRNA.
DR   CCDS; CCDS21948.1; -.
DR   RefSeq; NP_075629.2; NM_023140.5.
DR   PDB; 1WIK; NMR; -; A=241-336.
DR   PDBsum; 1WIK; -.
DR   AlphaFoldDB; Q9CQM9; -.
DR   SMR; Q9CQM9; -.
DR   BioGRID; 206004; 8.
DR   IntAct; Q9CQM9; 4.
DR   MINT; Q9CQM9; -.
DR   STRING; 10090.ENSMUSP00000066621; -.
DR   GlyGen; Q9CQM9; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q9CQM9; -.
DR   PhosphoSitePlus; Q9CQM9; -.
DR   SwissPalm; Q9CQM9; -.
DR   REPRODUCTION-2DPAGE; IPI00315550; -.
DR   REPRODUCTION-2DPAGE; Q9CQM9; -.
DR   EPD; Q9CQM9; -.
DR   jPOST; Q9CQM9; -.
DR   MaxQB; Q9CQM9; -.
DR   PaxDb; 10090-ENSMUSP00000066621; -.
DR   PeptideAtlas; Q9CQM9; -.
DR   ProteomicsDB; 267635; -.
DR   Pumba; Q9CQM9; -.
DR   Antibodypedia; 32521; 414 antibodies from 31 providers.
DR   DNASU; 30926; -.
DR   Ensembl; ENSMUST00000064404.8; ENSMUSP00000066621.7; ENSMUSG00000031068.9.
DR   GeneID; 30926; -.
DR   KEGG; mmu:30926; -.
DR   UCSC; uc009kew.1; mouse.
DR   AGR; MGI:1353653; -.
DR   MGI; MGI:1353653; Glrx3.
DR   VEuPathDB; HostDB:ENSMUSG00000031068; -.
DR   eggNOG; KOG0911; Eukaryota.
DR   GeneTree; ENSGT00550000075030; -.
DR   HOGENOM; CLU_026126_12_2_1; -.
DR   InParanoid; Q9CQM9; -.
DR   OMA; CEPCTAV; -.
DR   OrthoDB; 1038at2759; -.
DR   PhylomeDB; Q9CQM9; -.
DR   TreeFam; TF314151; -.
DR   BioGRID-ORCS; 30926; 16 hits in 79 CRISPR screens.
DR   ChiTaRS; Glrx3; mouse.
DR   EvolutionaryTrace; Q9CQM9; -.
DR   PRO; PR:Q9CQM9; -.
DR   Proteomes; UP000000589; Chromosome 7.
DR   RNAct; Q9CQM9; Protein.
DR   Bgee; ENSMUSG00000031068; Expressed in embryonic brain and 142 other cell types or tissues.
DR   ExpressionAtlas; Q9CQM9; baseline and differential.
DR   GO; GO:0005938; C:cell cortex; IEA:UniProtKB-SubCell.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0030425; C:dendrite; ISO:MGI.
DR   GO; GO:1990229; C:iron-sulfur cluster assembly complex; ISO:MGI.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0030018; C:Z disc; IDA:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR   GO; GO:0051536; F:iron-sulfur cluster binding; IEA:UniProtKB-KW.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0005080; F:protein kinase C binding; ISO:MGI.
DR   GO; GO:0044571; P:[2Fe-2S] cluster assembly; ISS:UniProtKB.
DR   GO; GO:0045454; P:cell redox homeostasis; ISO:MGI.
DR   GO; GO:0006879; P:intracellular iron ion homeostasis; ISO:MGI.
DR   GO; GO:0016226; P:iron-sulfur cluster assembly; ISO:MGI.
DR   GO; GO:0010614; P:negative regulation of cardiac muscle hypertrophy; IMP:UniProtKB.
DR   GO; GO:0097428; P:protein maturation by iron-sulfur cluster transfer; ISS:UniProtKB.
DR   GO; GO:0002026; P:regulation of the force of heart contraction; IMP:UniProtKB.
DR   CDD; cd03028; GRX_PICOT_like; 2.
DR   CDD; cd02984; TRX_PICOT; 1.
DR   Gene3D; 3.40.30.10; Glutaredoxin; 3.
DR   InterPro; IPR002109; Glutaredoxin.
DR   InterPro; IPR033658; GRX_PICOT-like.
DR   InterPro; IPR004480; Monothiol_GRX-rel.
DR   InterPro; IPR036249; Thioredoxin-like_sf.
DR   InterPro; IPR013766; Thioredoxin_domain.
DR   NCBIfam; TIGR00365; Grx4 family monothiol glutaredoxin; 1.
DR   PANTHER; PTHR10293; GLUTAREDOXIN FAMILY MEMBER; 1.
DR   PANTHER; PTHR10293:SF73; GLUTAREDOXIN-3; 1.
DR   Pfam; PF00462; Glutaredoxin; 2.
DR   Pfam; PF00085; Thioredoxin; 1.
DR   SUPFAM; SSF52833; Thioredoxin-like; 3.
DR   PROSITE; PS51354; GLUTAREDOXIN_2; 2.
DR   PROSITE; PS51352; THIOREDOXIN_2; 1.
DR   Genevisible; Q9CQM9; MM.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Cytoplasm; Direct protein sequencing; Iron;
KW   Iron-sulfur; Metal-binding; Phosphoprotein; Reference proteome; Repeat.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000250|UniProtKB:O76003"
FT   CHAIN           2..337
FT                   /note="Glutaredoxin-3"
FT                   /id="PRO_0000120020"
FT   DOMAIN          2..119
FT                   /note="Thioredoxin"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00691"
FT   DOMAIN          144..238
FT                   /note="Glutaredoxin 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00686"
FT   DOMAIN          239..337
FT                   /note="Glutaredoxin 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00686"
FT   BINDING         161
FT                   /ligand="[2Fe-2S] cluster"
FT                   /ligand_id="ChEBI:CHEBI:190135"
FT                   /ligand_note="ligand shared between dimeric partners"
FT                   /evidence="ECO:0000250|UniProtKB:O76003"
FT   BINDING         263
FT                   /ligand="[2Fe-2S] cluster"
FT                   /ligand_id="ChEBI:CHEBI:190135"
FT                   /ligand_note="ligand shared between dimeric partners"
FT                   /evidence="ECO:0000250|UniProtKB:O76003"
FT   MOD_RES         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0000250|UniProtKB:O76003"
FT   MOD_RES         119
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O76003"
FT   CONFLICT        76
FT                   /note="P -> T (in Ref. 1; AAF28842)"
FT                   /evidence="ECO:0000305"
FT   HELIX           241..245
FT                   /evidence="ECO:0007829|PDB:1WIK"
FT   STRAND          248..256
FT                   /evidence="ECO:0007829|PDB:1WIK"
FT   TURN            257..259
FT                   /evidence="ECO:0007829|PDB:1WIK"
FT   HELIX           266..275
FT                   /evidence="ECO:0007829|PDB:1WIK"
FT   STRAND          280..287
FT                   /evidence="ECO:0007829|PDB:1WIK"
FT   HELIX           289..299
FT                   /evidence="ECO:0007829|PDB:1WIK"
FT   STRAND          306..308
FT                   /evidence="ECO:0007829|PDB:1WIK"
FT   STRAND          310..315
FT                   /evidence="ECO:0007829|PDB:1WIK"
FT   HELIX           317..326
FT                   /evidence="ECO:0007829|PDB:1WIK"
FT   HELIX           330..334
FT                   /evidence="ECO:0007829|PDB:1WIK"
SQ   SEQUENCE   337 AA;  37778 MW;  74A1C65621B28FA0 CRC64;
     MAAGAAEAGE AAVAVVEVGS AQQFEELLRL KTKSLLVVHF WAPWAPQCVQ MNDVMAELAK
     EHPHVSFVKL EAEAVPEVSE KYEISSVPTF LFFKNSQKVD RLDGAHAPEL TKKVQRHVSS
     GAFPPSTNEH LKEDLSLRLK KLTHAAPCML FMKGTPQEPR CGFSKQMVEI LHKHNIQFSS
     FDIFSDEEVR QGLKTYSNWP TYPQLYVSGE LIGGLDIIKE LEASEELDTI CPKAPKLEER
     LKVLTNKASV MLFMKGNKQE AKCGFSKQIL EILNSTGVEY ETFDILEDEE VRQGLKTFSN
     WPTYPQLYVR GDLVGGLDIV KELKDNGELL PILKGEN
//