ID   BEX3_MOUSE              Reviewed;         124 AA.
AC   Q9WTZ9; A3KGA0; A3KGA1; Q9CWN9; Q9D0S2; Q9D1N5;
DT   04-APR-2006, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1999, sequence version 1.
DT   08-NOV-2023, entry version 143.
DE   RecName: Full=Protein BEX3 {ECO:0000305};
DE   AltName: Full=Brain-expressed X-linked protein 3 homolog {ECO:0000250|UniProtKB:Q00994};
DE   AltName: Full=Nerve growth factor receptor-associated protein 1;
DE   AltName: Full=p75NTR-associated cell death executor {ECO:0000303|PubMed:10764727};
GN   Name=Bex3 {ECO:0000303|PubMed:34562363, ECO:0000312|MGI:MGI:1338016};
GN   Synonyms=Nade {ECO:0000303|PubMed:10764727}, Ngfrap1;
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] (ISOFORM 1).
RC   STRAIN=FVB/N;
RX   PubMed=10072429; DOI=10.1093/hmg/8.4.611;
RA   Brown A.L., Kay G.F.;
RT   "Bex1, a gene with increased expression in parthenogenetic embryos, is a
RT   member of a novel gene family on the mouse X chromosome.";
RL   Hum. Mol. Genet. 8:611-619(1999).
RN   [2]
RP   ERRATUM OF PUBMED:10072429.
RA   Brown A.L., Kay G.F.;
RL   Hum. Mol. Genet. 8:943-943(1999).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION, AND
RP   DEGRADATION BY THE PROTEASOME.
RC   STRAIN=BALB/cJ;
RX   PubMed=10764727; DOI=10.1074/jbc.c000140200;
RA   Mukai J., Hachiya T., Shoji-Hoshino S., Kimura M.T., Nadano D., Suvanto P.,
RA   Hanaoka T., Li Y., Irie S., Greene L.A., Sato T.-A.;
RT   "NADE, a p75NTR-associated cell death executor, is involved in signal
RT   transduction mediated by the common neurotrophin receptor p75NTR.";
RL   J. Biol. Chem. 275:17566-17570(2000).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   STRAIN=C57BL/6J;
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   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=C57BL/6J;
RX   PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA   Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA   Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA   Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA   Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA   Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA   Eichler E.E., Ponting C.P.;
RT   "Lineage-specific biology revealed by a finished genome assembly of the
RT   mouse.";
RL   PLoS Biol. 7:E1000112-E1000112(2009).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   STRAIN=FVB/N; TISSUE=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   [7]
RP   INTERACTION WITH YWHAE.
RX   PubMed=11278287; DOI=10.1074/jbc.m005453200;
RA   Kimura M.T., Irie S., Shoji-Hoshino S., Mukai J., Nadano D., Oshimura M.,
RA   Sato T.-A.;
RT   "14-3-3 is involved in p75 neurotrophin receptor-mediated signal
RT   transduction.";
RL   J. Biol. Chem. 276:17291-17300(2001).
RN   [8]
RP   SUBCELLULAR LOCATION, SUBUNIT, INTERACTION WITH NGFR, AND MUTAGENESIS OF
RP   LEU-94; LEU-97 AND LEU-99.
RX   PubMed=11830582; DOI=10.1074/jbc.m106342200;
RA   Mukai J., Shoji S., Kimura M.T., Okubo S., Sano H., Suvanto P., Li Y.,
RA   Irie S., Sato T.-A.;
RT   "Structure-function analysis of NADE: identification of regions that
RT   mediate nerve growth factor-induced apoptosis.";
RL   J. Biol. Chem. 277:13973-13982(2002).
RN   [9]
RP   TISSUE SPECIFICITY.
RX   PubMed=12935912; DOI=10.1016/s0165-3806(03)00166-4;
RA   Kendall S.E., Ryczko M.C., Mehan M., Verdi J.M.;
RT   "Characterization of NADE, NRIF and SC-1 gene expression during mouse
RT   neurogenesis.";
RL   Brain Res. Dev. Brain Res. 144:151-158(2003).
RN   [10]
RP   INTERACTION WITH DIABLO.
RX   PubMed=15178455; DOI=10.1016/j.bbrc.2004.05.043;
RA   Yoon K., Jang H.D., Lee S.Y.;
RT   "Direct interaction of Smac with NADE promotes TRAIL-induced apoptosis.";
RL   Biochem. Biophys. Res. Commun. 319:649-654(2004).
RN   [11]
RP   SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND MUTAGENESIS OF CYS-121.
RX   PubMed=15563833; DOI=10.1016/j.gene.2004.08.031;
RA   Kim A.-J., Lee C.-S., Schlessinger D.;
RT   "Bex3 associates with replicating mitochondria and is involved in possible
RT   growth control of F9 teratocarcinoma cells.";
RL   Gene 343:79-89(2004).
RN   [12]
RP   FUNCTION, ZINC-BINDING, AND MUTAGENESIS OF 113-HIS--HIS-117 AND CYS-121.
RX   PubMed=34562363; DOI=10.1016/j.cell.2021.09.002;
RA   Manford A.G., Mena E.L., Shih K.Y., Gee C.L., McMinimy R.,
RA   Martinez-Gonzalez B., Sherriff R., Lew B., Zoltek M., Rodriguez-Perez F.,
RA   Woldesenbet M., Kuriyan J., Rape M.;
RT   "Structural basis and regulation of the reductive stress response.";
RL   Cell 184:5375-5390(2021).
CC   -!- FUNCTION: May be a signaling adapter molecule involved in NGFR/p75NTR-
CC       mediated apoptosis induced by NGF (PubMed:10764727). Plays a role in
CC       zinc-triggered neuronal death (PubMed:10764727). In absence of
CC       reductive stress, acts as a pseudosubstrate for the CRL2(FEM1B)
CC       complex: associates with FEM1B via zinc, thereby preventing association
CC       between FEM1B and its substrates (PubMed:34562363).
CC       {ECO:0000269|PubMed:10764727, ECO:0000269|PubMed:34562363}.
CC   -!- SUBUNIT: Self-associates (PubMed:11830582). Binds to the DEATH domain
CC       of p75NTR/NGFR (PubMed:11830582). Interacts with 14-3-3 epsilon (YWHAE)
CC       (PubMed:11278287). Interacts with DIABLO/SMAC (PubMed:15178455).
CC       {ECO:0000269|PubMed:11278287, ECO:0000269|PubMed:11830582,
CC       ECO:0000269|PubMed:15178455}.
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11830582}. Cytoplasm,
CC       cytosol {ECO:0000269|PubMed:10764727, ECO:0000269|PubMed:11830582}.
CC       Note=Shuttles between the cytoplasm and the nucleus (PubMed:11830582).
CC       Associates with replicating mitochondria (PubMed:15563833).
CC       {ECO:0000269|PubMed:11830582, ECO:0000269|PubMed:15563833}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q9WTZ9-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q9WTZ9-2; Sequence=VSP_017744;
CC   -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:12935912,
CC       ECO:0000269|PubMed:15563833}.
CC   -!- DOMAIN: The nuclear export signal is required for export from the
CC       nucleus and the interactions with itself and NGFR/p75NTR.
CC       {ECO:0000269|PubMed:11830582}.
CC   -!- DOMAIN: The histidine cluster (His cluster) and Cys-121 mediate zinc-
CC       binding. {ECO:0000269|PubMed:34562363}.
CC   -!- PTM: Ubiquitinated (PubMed:10764727). Degraded by the proteasome
CC       (PubMed:10764727). {ECO:0000269|PubMed:10764727, ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the BEX family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAB23350.1; Type=Erroneous termination; Note=Extended C-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AF097440; AAD24431.1; -; mRNA.
DR   EMBL; AF187066; AAF75131.1; -; mRNA.
DR   EMBL; AK003294; BAB22697.1; -; mRNA.
DR   EMBL; AK004531; BAB23350.1; ALT_SEQ; mRNA.
DR   EMBL; AK010500; BAB26986.1; -; mRNA.
DR   EMBL; AL671493; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC027815; AAH27815.1; -; mRNA.
DR   CCDS; CCDS30419.1; -. [Q9WTZ9-1]
DR   CCDS; CCDS53194.1; -. [Q9WTZ9-2]
DR   RefSeq; NP_001103703.1; NM_001110233.1. [Q9WTZ9-1]
DR   RefSeq; NP_001103704.1; NM_001110234.1. [Q9WTZ9-2]
DR   RefSeq; NP_033880.1; NM_009750.2. [Q9WTZ9-1]
DR   AlphaFoldDB; Q9WTZ9; -.
DR   BioGRID; 198339; 9.
DR   STRING; 10090.ENSMUSP00000063039; -.
DR   PhosphoSitePlus; Q9WTZ9; -.
DR   PaxDb; 10090-ENSMUSP00000063039; -.
DR   Antibodypedia; 540; 282 antibodies from 36 providers.
DR   DNASU; 12070; -.
DR   Ensembl; ENSMUST00000053540; ENSMUSP00000063039; ENSMUSG00000046432. [Q9WTZ9-1]
DR   Ensembl; ENSMUST00000113112; ENSMUSP00000108737; ENSMUSG00000046432. [Q9WTZ9-2]
DR   Ensembl; ENSMUST00000113113; ENSMUSP00000108738; ENSMUSG00000046432. [Q9WTZ9-1]
DR   Ensembl; ENSMUST00000178632; ENSMUSP00000136952; ENSMUSG00000046432. [Q9WTZ9-1]
DR   GeneID; 12070; -.
DR   KEGG; mmu:12070; -.
DR   UCSC; uc009uik.2; mouse. [Q9WTZ9-1]
DR   AGR; MGI:1338016; -.
DR   CTD; 27018; -.
DR   MGI; MGI:1338016; Bex3.
DR   VEuPathDB; HostDB:ENSMUSG00000046432; -.
DR   eggNOG; ENOG502TF4N; Eukaryota.
DR   GeneTree; ENSGT00940000153412; -.
DR   HOGENOM; CLU_123122_0_0_1; -.
DR   InParanoid; Q9WTZ9; -.
DR   OMA; EMEQHMQ; -.
DR   OrthoDB; 5262794at2759; -.
DR   PhylomeDB; Q9WTZ9; -.
DR   TreeFam; TF337909; -.
DR   Reactome; R-MMU-205025; NADE modulates death signalling.
DR   BioGRID-ORCS; 12070; 2 hits in 76 CRISPR screens.
DR   ChiTaRS; Ngfrap1; mouse.
DR   PRO; PR:Q9WTZ9; -.
DR   Proteomes; UP000000589; Chromosome X.
DR   RNAct; Q9WTZ9; Protein.
DR   Bgee; ENSMUSG00000046432; Expressed in yolk sac and 245 other tissues.
DR   Genevisible; Q9WTZ9; MM.
DR   GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR   GO; GO:0005829; C:cytosol; IDA:MGI.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0005123; F:death receptor binding; IPI:MGI.
DR   GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0140678; F:molecular function inhibitor activity; IDA:UniProtKB.
DR   GO; GO:0005163; F:nerve growth factor receptor binding; ISO:MGI.
DR   GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR   GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IPI:MGI.
DR   GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB.
DR   GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR   InterPro; IPR007623; BEX.
DR   InterPro; IPR021156; TF_A-like/BEX.
DR   PANTHER; PTHR19430; PROTEIN BEX1-RELATED; 1.
DR   PANTHER; PTHR19430:SF1; PROTEIN BEX3; 1.
DR   Pfam; PF04538; BEX; 1.
DR   PIRSF; PIRSF008633; BEX; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Apoptosis; Cytoplasm; Metal-binding; Nucleus;
KW   Reference proteome; Ubl conjugation; Zinc.
FT   CHAIN           1..124
FT                   /note="Protein BEX3"
FT                   /id="PRO_0000229781"
FT   REGION          1..56
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          81..124
FT                   /note="Interaction with 14-3-3 epsilon"
FT                   /evidence="ECO:0000269|PubMed:11278287"
FT   REGION          81..106
FT                   /note="Interaction with p75NTR/NGFR"
FT                   /evidence="ECO:0000269|PubMed:11830582"
FT   REGION          113..117
FT                   /note="His cluster"
FT                   /evidence="ECO:0000269|PubMed:34562363"
FT   MOTIF           90..100
FT                   /note="Nuclear export signal"
FT                   /evidence="ECO:0000269|PubMed:11830582"
FT   BINDING         121
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="ligand shared with FEM1B"
FT                   /evidence="ECO:0000269|PubMed:34562363"
FT   VAR_SEQ         1..10
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:16141072"
FT                   /id="VSP_017744"
FT   MUTAGEN         94
FT                   /note="L->A: Abolishes nuclear export and interactions with
FT                   itself and p75NTR/NGFR; when associated with A-97 and A-
FT                   99."
FT                   /evidence="ECO:0000269|PubMed:11830582"
FT   MUTAGEN         97
FT                   /note="L->A: Abolishes nuclear export and interactions with
FT                   itself and p75NTR/NGFR; when associated with A-97 and A-
FT                   99."
FT                   /evidence="ECO:0000269|PubMed:11830582"
FT   MUTAGEN         99
FT                   /note="L->A: Abolishes nuclear export and interactions with
FT                   itself and p75NTR/NGFR; when associated with A-94 and A-
FT                   97."
FT                   /evidence="ECO:0000269|PubMed:11830582"
FT   MUTAGEN         113..117
FT                   /note="HHDHH->AADAA: Abolished zinc-binding and association
FT                   with FEM1B."
FT                   /evidence="ECO:0000269|PubMed:34562363"
FT   MUTAGEN         121
FT                   /note="C->A: Abolishes localization with replicating
FT                   mitochondria."
FT                   /evidence="ECO:0000269|PubMed:15563833"
FT   MUTAGEN         121
FT                   /note="C->S: Abolished zinc-binding and association with
FT                   FEM1B."
FT                   /evidence="ECO:0000269|PubMed:34562363"
FT   CONFLICT        17
FT                   /note="N -> D (in Ref. 4; BAB26986)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        82
FT                   /note="M -> I (in Ref. 4; BAB22697)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   124 AA;  14542 MW;  3CCCD4F05E66F461 CRC64;
     MANVHQENEE MEQPLQNGQE DRPVGGGEGH QPAANNNNNN HNHNHNHHRR GQARRLAPNF
     RWAIPNRQMN DGLGGDGDDM EMFMEEMREI RRKLRELQLR NCLRILMGEL SNHHDHHDEF
     CLMP
//