ID BBC3_HUMAN Reviewed; 193 AA.
AC Q9BXH1; B9EGI3; O00171; Q96PG9;
DT 21-DEC-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 27-MAR-2024, entry version 170.
DE RecName: Full=Bcl-2-binding component 3, isoforms 1/2;
DE AltName: Full=JFY-1;
DE AltName: Full=p53 up-regulated modulator of apoptosis;
GN Name=BBC3; Synonyms=PUMA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION,
RP INTERACTION WITH BCL2 AND BCL2L1, AND TISSUE SPECIFICITY.
RX PubMed=11463391; DOI=10.1016/s1097-2765(01)00213-1;
RA Yu J., Zhang L., Hwang P.M., Kinzler K.W., Vogelstein B.;
RT "PUMA induces the rapid apoptosis of colorectal cancer cells.";
RL Mol. Cell 7:673-682(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3 AND 4), FUNCTION, INTERACTION
RP WITH BCL2, INDUCTION BY TP53, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP 141-LEU--ARG-143.
RX PubMed=11463392; DOI=10.1016/s1097-2765(01)00214-3;
RA Nakano K., Wousden K.H.;
RT "PUMA, a novel proapoptotic gene, is induced by p53.";
RL Mol. Cell 7:683-694(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INDUCTION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=11572983; DOI=10.1073/pnas.201208798;
RA Han J.-W., Flemington C., Houghton A.B., Gu Z., Zambetti G.P., Lutz R.J.,
RA Zhu L., Chittenden T.;
RT "Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse
RT cell death and survival signals.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:11318-11323(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
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 [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [7]
RP INDUCTION.
RX PubMed=22761832; DOI=10.1371/journal.pone.0039586;
RA Ghosh A.P., Klocke B.J., Ballestas M.E., Roth K.A.;
RT "CHOP potentially co-operates with FOXO3a in neuronal cells to regulate
RT PUMA and BIM expression in response to ER stress.";
RL PLoS ONE 7:E39586-E39586(2012).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 130-154 IN COMPLEX WITH BCL2L1,
RP STRUCTURE BY NMR OF 130-154 IN COMPLEX WITH BCL2L1, FUNCTION, DOMAIN,
RP MUTAGENESIS OF TRP-133, AND INTERACTION WITH BCL2L1.
RX PubMed=23340338; DOI=10.1038/nchembio.1166;
RA Follis A.V., Chipuk J.E., Fisher J.C., Yun M.K., Grace C.R., Nourse A.,
RA Baran K., Ou L., Min L., White S.W., Green D.R., Kriwacki R.W.;
RT "PUMA binding induces partial unfolding within BCL-xL to disrupt p53
RT binding and promote apoptosis.";
RL Nat. Chem. Biol. 9:163-168(2013).
CC -!- FUNCTION: Essential mediator of p53/TP53-dependent and p53/TP53-
CC independent apoptosis (PubMed:11463391, PubMed:23340338). Promotes
CC partial unfolding of BCL2L1 and dissociation of BCL2L1 from p53/TP53,
CC releasing the bound p53/TP53 to induce apoptosis (PubMed:23340338).
CC Regulates ER stress-induced neuronal apoptosis (By similarity).
CC {ECO:0000250|UniProtKB:Q99ML1, ECO:0000269|PubMed:11463391,
CC ECO:0000269|PubMed:23340338}.
CC -!- SUBUNIT: Interacts with MCL1 and BCL2A1 (By similarity). Interacts (via
CC BH3 domain) with BCL2 (PubMed:11463391). Interacts with BCL2L1/BCL-XL
CC (PubMed:23340338). Interacts (via BH3 domain) with NOL3/ARC (via CARD
CC domain); this interaction prevents BBC3 association with BCL2 and
CC results in CASP8 activation (By similarity).
CC {ECO:0000250|UniProtKB:Q80ZG6, ECO:0000250|UniProtKB:Q99ML1,
CC ECO:0000269|PubMed:11463391, ECO:0000269|PubMed:23340338}.
CC -!- INTERACTION:
CC Q9BXH1; P10415: BCL2; NbExp=6; IntAct=EBI-519884, EBI-77694;
CC Q9BXH1; Q07817-1: BCL2L1; NbExp=9; IntAct=EBI-519884, EBI-287195;
CC Q9BXH1; Q92843: BCL2L2; NbExp=3; IntAct=EBI-519884, EBI-707714;
CC Q9BXH1; P00533: EGFR; NbExp=10; IntAct=EBI-519884, EBI-297353;
CC Q9BXH1; Q07820: MCL1; NbExp=5; IntAct=EBI-519884, EBI-1003422;
CC Q9BXH1; P97287: Mcl1; Xeno; NbExp=5; IntAct=EBI-519884, EBI-707292;
CC Q9BXH1-2; Q07820: MCL1; NbExp=2; IntAct=EBI-519896, EBI-1003422;
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:11463391,
CC ECO:0000269|PubMed:11463392, ECO:0000269|PubMed:11572983}.
CC Note=Localized to the mitochondria in order to induce cytochrome c
CC release.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=PUMA alpha;
CC IsoId=Q9BXH1-1; Sequence=Displayed;
CC Name=2; Synonyms=PUMA beta;
CC IsoId=Q9BXH1-2; Sequence=VSP_012238;
CC Name=3; Synonyms=PUMA delta;
CC IsoId=Q96PG8-1; Sequence=External;
CC Name=4; Synonyms=PUMA gamma;
CC IsoId=Q96PG8-2; Sequence=External;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC {ECO:0000269|PubMed:11463391}.
CC -!- INDUCTION: Up-regulated by TP53 (PubMed:11463392, PubMed:11572983). Up-
CC regulated by DNA damage, glucocorticoid treatment and growth factor
CC deprivation (PubMed:11572983). Up-regulated by ER stress in a
CC DDIT3/CHOP-dependent manner (PubMed:22761832).
CC {ECO:0000269|PubMed:11463392, ECO:0000269|PubMed:11572983,
CC ECO:0000269|PubMed:22761832}.
CC -!- DOMAIN: The BH3 motif is intrinsically disordered in the absence of a
CC binding partner but folds upon binding (PubMed:23340338). Folds when
CC bound to BCL2L1 (PubMed:23340338). Also folds when bound to MCL1 (By
CC similarity). {ECO:0000250|UniProtKB:Q99ML1,
CC ECO:0000269|PubMed:23340338}.
CC -!- SIMILARITY: Belongs to the Bcl-2 family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="https://atlasgeneticsoncology.org/gene/759/bbc3-(bcl2-binding-component-3)";
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DR EMBL; AF332558; AAK31316.1; -; mRNA.
DR EMBL; AF354654; AAK39542.1; -; mRNA.
DR EMBL; AF354655; AAK39543.1; -; mRNA.
DR EMBL; U82987; AAB51243.2; -; mRNA.
DR EMBL; CH471126; EAW57465.1; -; Genomic_DNA.
DR EMBL; BC136481; AAI36482.1; -; mRNA.
DR CCDS; CCDS12697.1; -. [Q9BXH1-1]
DR CCDS; CCDS46130.1; -. [Q9BXH1-2]
DR RefSeq; NP_001120712.1; NM_001127240.2.
DR RefSeq; NP_001120713.1; NM_001127241.2. [Q9BXH1-2]
DR RefSeq; NP_001120714.1; NM_001127242.2.
DR RefSeq; NP_055232.1; NM_014417.4. [Q9BXH1-1]
DR RefSeq; XP_006723204.1; XM_006723141.3. [Q9BXH1-1]
DR PDB; 2M04; NMR; -; B=130-154.
DR PDB; 4BPI; X-ray; 1.98 A; B=136-152.
DR PDB; 4BPJ; X-ray; 1.60 A; D=139-153.
DR PDB; 4BPK; X-ray; 1.76 A; C/D=134-152.
DR PDB; 4HNJ; X-ray; 2.90 A; C=130-154.
DR PDB; 5UUL; X-ray; 1.33 A; B=132-154.
DR PDB; 6QFM; X-ray; 2.00 A; B=127-149.
DR PDB; 6QG8; X-ray; 1.90 A; B=127-149.
DR PDB; 6TQP; X-ray; 1.85 A; B=130-155.
DR PDB; 7DVD; X-ray; 2.59 A; E=136-150.
DR PDB; 7P0S; X-ray; 2.50 A; C/U=130-155.
DR PDB; 7P9W; X-ray; 2.00 A; B=130-155.
DR PDB; 7QTX; X-ray; 2.12 A; B=130-155.
DR PDBsum; 2M04; -.
DR PDBsum; 4BPI; -.
DR PDBsum; 4BPJ; -.
DR PDBsum; 4BPK; -.
DR PDBsum; 4HNJ; -.
DR PDBsum; 5UUL; -.
DR PDBsum; 6QFM; -.
DR PDBsum; 6QG8; -.
DR PDBsum; 6TQP; -.
DR PDBsum; 7DVD; -.
DR PDBsum; 7P0S; -.
DR PDBsum; 7P9W; -.
DR PDBsum; 7QTX; -.
DR AlphaFoldDB; Q9BXH1; -.
DR SMR; Q9BXH1; -.
DR BioGRID; 118009; 35.
DR ComplexPortal; CPX-1986; PUMA:BCL-2 complex.
DR ComplexPortal; CPX-1987; PUMA:BCL-XL complex.
DR DIP; DIP-29215N; -.
DR IntAct; Q9BXH1; 10.
DR MINT; Q9BXH1; -.
DR iPTMnet; Q9BXH1; -.
DR PhosphoSitePlus; Q9BXH1; -.
DR BioMuta; BBC3; -.
DR DMDM; 56748610; -.
DR EPD; Q9BXH1; -.
DR jPOST; Q9BXH1; -.
DR MassIVE; Q9BXH1; -.
DR MaxQB; Q9BXH1; -.
DR PeptideAtlas; Q9BXH1; -.
DR ProteomicsDB; 79423; -. [Q9BXH1-1]
DR ProteomicsDB; 79424; -. [Q9BXH1-2]
DR Pumba; Q9BXH1; -.
DR Antibodypedia; 3572; 889 antibodies from 43 providers.
DR DNASU; 27113; -.
DR Ensembl; ENST00000341983.8; ENSP00000341155.4; ENSG00000105327.18. [Q9BXH1-2]
DR Ensembl; ENST00000439096.3; ENSP00000395862.2; ENSG00000105327.18. [Q9BXH1-1]
DR GeneID; 27113; -.
DR KEGG; hsa:27113; -.
DR MANE-Select; ENST00000439096.3; ENSP00000395862.2; NM_014417.5; NP_055232.1.
DR UCSC; uc002pgf.5; human. [Q9BXH1-1]
DR AGR; HGNC:17868; -.
DR CTD; 27113; -.
DR DisGeNET; 27113; -.
DR GeneCards; BBC3; -.
DR HGNC; HGNC:17868; BBC3.
DR HPA; ENSG00000105327; Low tissue specificity.
DR MIM; 605854; gene.
DR neXtProt; NX_Q9BXH1; -.
DR OpenTargets; ENSG00000105327; -.
DR PharmGKB; PA38471; -.
DR VEuPathDB; HostDB:ENSG00000105327; -.
DR GeneTree; ENSGT00390000002767; -.
DR HOGENOM; CLU_158732_0_0_1; -.
DR OrthoDB; 4740984at2759; -.
DR PhylomeDB; Q9BXH1; -.
DR PathwayCommons; Q9BXH1; -.
DR Reactome; R-HSA-111453; BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members.
DR Reactome; R-HSA-139915; Activation of PUMA and translocation to mitochondria.
DR Reactome; R-HSA-6803204; TP53 Regulates Transcription of Genes Involved in Cytochrome C Release.
DR Reactome; R-HSA-9614657; FOXO-mediated transcription of cell death genes.
DR SignaLink; Q9BXH1; -.
DR SIGNOR; Q9BXH1; -.
DR BioGRID-ORCS; 27113; 22 hits in 1161 CRISPR screens.
DR ChiTaRS; BBC3; human.
DR GenomeRNAi; 27113; -.
DR Pharos; Q9BXH1; Tbio.
DR Proteomes; UP000005640; Chromosome 19.
DR Bgee; ENSG00000105327; Expressed in type B pancreatic cell and 182 other cell types or tissues.
DR ExpressionAtlas; Q9BXH1; baseline and differential.
DR Genevisible; Q9BXH1; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0097190; P:apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0071456; P:cellular response to hypoxia; IEP:UniProtKB.
DR GO; GO:0071479; P:cellular response to ionizing radiation; IEA:Ensembl.
DR GO; GO:0008340; P:determination of adult lifespan; ISS:BHF-UCL.
DR GO; GO:0006974; P:DNA damage response; ISS:BHF-UCL.
DR GO; GO:0097194; P:execution phase of apoptosis; IDA:UniProtKB.
DR GO; GO:0044346; P:fibroblast apoptotic process; IEA:Ensembl.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IEA:Ensembl.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; IDA:ParkinsonsUK-UCL.
DR GO; GO:0045926; P:negative regulation of growth; IMP:UniProtKB.
DR GO; GO:2001056; P:positive regulation of cysteine-type endopeptidase activity; ISS:UniProtKB.
DR GO; GO:1902237; P:positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; TAS:ParkinsonsUK-UCL.
DR GO; GO:1903749; P:positive regulation of establishment of protein localization to mitochondrion; IEA:Ensembl.
DR GO; GO:2000271; P:positive regulation of fibroblast apoptotic process; IEA:Ensembl.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:1903896; P:positive regulation of IRE1-mediated unfolded protein response; TAS:ParkinsonsUK-UCL.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:BHF-UCL.
DR GO; GO:0090200; P:positive regulation of release of cytochrome c from mitochondria; IGI:BHF-UCL.
DR GO; GO:0070245; P:positive regulation of thymocyte apoptotic process; ISS:BHF-UCL.
DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IDA:UniProtKB.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IDA:UniProtKB.
DR GO; GO:0070231; P:T cell apoptotic process; IEA:Ensembl.
DR InterPro; IPR031661; Bbc3.
DR PANTHER; PTHR28639; BCL-2-BINDING COMPONENT 3; 1.
DR PANTHER; PTHR28639:SF1; BCL-2-BINDING COMPONENT 3, ISOFORMS 3_4; 1.
DR Pfam; PF15826; PUMA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Mitochondrion;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1..193
FT /note="Bcl-2-binding component 3, isoforms 1/2"
FT /id="PRO_0000143083"
FT REGION 1..28
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 71..138
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 137..151
FT /note="BH3"
FT MOD_RES 10
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..92
FT /note="MARARQEGSSPEPVEGLARDGPRPFPLGRLVPSAVSCGLCEPGLAAAPAAPT
FT LLPAAYLCAPTAPPAVTAALGGSRWPGGPRSRPRGPRPDG -> MKFGMGSAQACPCQV
FT PRAASTTWVPCQICG (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11463392"
FT /id="VSP_012238"
FT MUTAGEN 133
FT /note="W->A: Impairs p53/TP53-dependent apoptosis."
FT /evidence="ECO:0000269|PubMed:23340338"
FT MUTAGEN 141..143
FT /note="Missing: Abolishes BLC2-binding. Impairs growth
FT inhibitory activity. No effect on mitochondrial subcellular
FT location."
FT /evidence="ECO:0000269|PubMed:11463392"
FT HELIX 133..150
FT /evidence="ECO:0007829|PDB:5UUL"
FT TURN 151..154
FT /evidence="ECO:0007829|PDB:7P0S"
SQ SEQUENCE 193 AA; 20532 MW; 3585527F1858A4FA CRC64;
MARARQEGSS PEPVEGLARD GPRPFPLGRL VPSAVSCGLC EPGLAAAPAA PTLLPAAYLC
APTAPPAVTA ALGGSRWPGG PRSRPRGPRP DGPQPSLSLA EQHLESPVPS APGALAGGPT
QAAPGVRGEE EQWAREIGAQ LRRMADDLNA QYERRRQEEQ QRHRPSPWRV LYNLIMGLLP
LPRGHRAPEM EPN
//
