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Reviewed, UniProtKB/Swiss-Prot P10415 (BCL2_HUMAN)

Last modified November 3, 2009. Version 139. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Apoptosis regulator Bcl-2
Gene names
Name: BCL2
OrganismHomo sapiens (Human) [Complete proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length239 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).

Subunit structure

Forms homodimers, and heterodimers with BAX, BAD, BAK and Bcl-X(L). Heterodimerization with BAX requires intact BH1 and BH2 motifs, and is necessary for anti-apoptotic activity By similarity. Also interacts with APAF1, RAF-1, TP53BP2, BBC3, BCL2L1, MRPL41 and BNIPL. Binding to FKBP8 seems to target BCL2 to the mitochondria and probably interferes with the binding of BCL2 to its targets.

Subcellular location

Mitochondrion outer membrane; Single-pass membrane protein. Nucleus membrane; Single-pass membrane protein. Endoplasmic reticulum membrane; Single-pass membrane protein. Ref.9

Tissue specificity

Expressed in a variety of tissues.

Domain

The BH4 motif is required for anti-apoptotic activity and for interaction with RAF-1.

Post-translational modification

Phosphorylation/dephosphorylation on Ser-70 regulates anti-apoptotic activity. Growth factor-stimulated phosphorylation on Ser-70 by PKC is required for the anti-apoptosis activity and occurs during the G2/M phase of the cell cycle. In the absence of growth factors, BCL2 appears to be phosphorylated by other protein kinases such as ERKs and stress-activated kinases. Dephosphorylated by protein phosphatase 2A (PP2A) By similarity.

Proteolytically cleaved by caspases during apoptosis. The cleaved protein, lacking the BH4 motif, has pro-apoptotic activity, causes the release of cytochrome c into the cytosol promoting further caspase activity. Ref.11

Involvement in disease

A chromosomal aberration involving BCL2 may be a cause of follicular lymphoma (FL) [MIM:151430]; also known as type II chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.

Sequence similarities

Belongs to the Bcl-2 family.

Ontologies

Keywords
   Biological processApoptosis
   Cellular componentEndoplasmic reticulum
Membrane
Mitochondrion
Mitochondrion outer membrane
Nucleus
   Coding sequence diversityAlternative splicing
Chromosomal rearrangement
Polymorphism
   DiseaseDisease mutation
Proto-oncogene
   DomainTransmembrane
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Gene Ontology (GO)
   Biological processB cell proliferation

Inferred from direct assay. Source: MGI

activation of pro-apoptotic gene products

Inferred from Experiment. Source: Reactome

anti-apoptosis

Inferred from direct assay. Source: UniProtKB

apoptosis in response to endoplasmic reticulum stress

Inferred from direct assay. Source: MGI

defense response to virus

Inferred from direct assay. Source: UniProtKB

female pregnancy

Non-traceable author statement. Source: UniProtKB

humoral immune response

Traceable author statement. Source: UniProtKB

negative regulation of cellular pH reduction

Inferred from direct assay. Source: UniProtKB

negative regulation of mitochondrial depolarization

Traceable author statement. Source: UniProtKB

negative regulation of neuron apoptosis

Inferred from direct assay. Source: MGI

neuron apoptosis

Traceable author statement. Source: HGNC

regulation of mitochondrial membrane permeability

Inferred from sequence or structural similarity. Source: HGNC

regulation of mitochondrial membrane potential

Inferred from sequence or structural similarity. Source: HGNC

regulation of protein heterodimerization activity

Inferred from direct assay. Source: UniProtKB

regulation of protein homodimerization activity

Inferred from direct assay. Source: UniProtKB

release of cytochrome c from mitochondria

Non-traceable author statement. Source: UniProtKB

response to cytokine stimulus

Inferred from direct assay. Source: MGI

response to drug

Inferred from direct assay. Source: MGI

response to iron ion

Inferred from direct assay. Source: UniProtKB

response to nicotine

Inferred from direct assay. Source: UniProtKB

response to toxin

Inferred from direct assay. Source: MGI

   Cellular componentintegral to membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

mitochondrial outer membrane

Inferred from direct assay. Source: UniProtKB

nuclear membrane

Inferred from direct assay. Source: UniProtKB

   Molecular functionBH3 domain binding

Inferred from physical interaction. Source: UniProtKB

protease binding

Inferred from direct assay. Source: UniProtKB

protein heterodimerization activity

Inferred from physical interaction. Source: UniProtKB

protein homodimerization activity

Inferred from direct assay. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform Alpha (identifier: P10415-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform Beta (identifier: P10415-2)

The sequence of this isoform differs from the canonical sequence as follows:
     196-239: DAFVELYGPSMRPLFDFSWLSLKTLLSLALVGACITLGAYLGHK → VGASGDVS

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 239239Apoptosis regulator Bcl-2
PRO_0000143048

Regions

Transmembrane212 – 23322 Potential
Motif10 – 3021BH4
Motif93 – 10715BH3
Motif136 – 15520BH1
Motif187 – 20216BH2

Sites

Site34 – 352Cleavage; by caspase-3

Amino acid modifications

Modified residue701Phosphoserine; by PKC By similarity

Natural variations

Alternative sequence196 – 23944DAFVE…YLGHK → VGASGDVS in isoform Beta.
VSP_000512
Natural variant71T → S
VAR_000827
Natural variant431A → T: dbSNP rs1800477. Ref.6
VAR_014716
Natural variant591P → S in non-Hodgkin lymphoma; somatic mutation. Ref.8
VAR_000828
Natural variant931V → I in non-Hodgkin lymphoma; somatic mutation. Ref.8
VAR_000829

Experimental info

Mutagenesis341D → A: Abolishes cleavage by caspase-3.
Mutagenesis641D → A: No effect on cleavage by caspase-3.
Mutagenesis1451G → A: No heterodimerization with BAX and loss of anti-apoptotic activity.
Mutagenesis1881W → A: No heterodimerization with BAX and loss of anti-apoptotic activity.
Sequence conflict481I → F in CAA29778. Ref.4
Sequence conflict591P → T in AAA35591. Ref.3
Sequence conflict961T → A in AAD14111. Ref.8
Sequence conflict1101R → G in AAD14111. Ref.8
Sequence conflict1171S → R in AAA35591. Ref.3
Sequence conflict1291R → C in CAA29778. Ref.4

Secondary structure

...................... 239
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform Alpha [UniParc].

Last modified April 1, 1993. Version 2.
Checksum: 3C49F2B714DC9CCB

FASTA23926,266
        10         20         30         40         50         60 
MAHAGRTGYD NREIVMKYIH YKLSQRGYEW DAGDVGAAPP GAAPAPGIFS SQPGHTPHPA 

        70         80         90        100        110        120 
ASRDPVARTS PLQTPAAPGA AAGPALSPVP PVVHLTLRQA GDDFSRRYRR DFAEMSSQLH 

       130        140        150        160        170        180 
LTPFTARGRF ATVVEELFRD GVNWGRIVAF FEFGGVMCVE SVNREMSPLV DNIALWMTEY 

       190        200        210        220        230 
LNRHLHTWIQ DNGGWDAFVE LYGPSMRPLF DFSWLSLKTL LSLALVGACI TLGAYLGHK 

« Hide

Isoform Beta.

Checksum: 2A271F901814EF69
Show »

FASTA20322,141

References

« Hide 'large scale' references
[1]"Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma."
Tsujimoto Y., Croce C.M.
Proc. Natl. Acad. Sci. U.S.A. 83:5214-5218(1986) [PubMed: 3523487] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ALPHA AND BETA).
[2]"Isolation and characterization of the chicken bcl-2 gene: expression in a variety of tissues including lymphoid and neuronal organs in adult and embryo."
Eguchi Y., Ewert D.L., Tsujimoto Y.
Nucleic Acids Res. 20:4187-4192(1992) [PubMed: 1508712] [Abstract]
Cited for: SEQUENCE REVISION TO 96; 110 AND 237.
[3]"Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation."
Cleary M.L., Smith S.D., Sklar J.
Cell 47:19-28(1986) [PubMed: 2875799] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA).
[4]"Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma."
Seto M., Jaeger U., Hockett R.D., Graninger W., Bennett S., Goldman P., Korsmeyer S.J.
EMBO J. 7:123-131(1988) [PubMed: 2834197] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA), VARIANT SER-7.
[5]"Consequences of the t(14;18) chromosomal translocation in follicular lymphoma: deregulated expression of a chimeric and mutated BCL-2 gene."
Hua C., Zorn S., Jensen J.P., Coupland R.W., Ko H.S., Wright J.J., Bakhshi A.
Oncogene Res. 2:263-275(1988) [PubMed: 3285301] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANT SER-7.
[6]NIEHS SNPs program
Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT THR-43.
[7]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA).
Tissue: Testis.
[8]"Frequent incidence of somatic mutations in translocated BCL2 oncogenes of non-Hodgkin's lymphomas."
Tanaka S., Louie D.C., Kant J.A., Reed J.C.
Blood 79:229-237(1992) [PubMed: 1339299] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-131 (ISOFORM ALPHA), VARIANTS NON-HODGKIN LYMPHOMA SER-59 AND ILE-93.
[9]"Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death."
Hockenbery D., Nunez G., Milliman C., Schreiber R.D., Korsmeyer S.J.
Nature 348:334-336(1990) [PubMed: 2250705] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[10]"BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax."
Yin X.-M., Oltvai Z.N., Korsmeyer S.J.
Nature 369:321-323(1994) [PubMed: 8183370] [Abstract]
Cited for: MUTAGENESIS.
[11]"Conversion of Bcl-2 to a Bax-like death effector by caspases."
Cheng E.H.-Y., Kirsch D.G., Clem R.J., Ravi R., Kastan M.B., Bedi A., Ueno K., Hardwick J.M.
Science 278:1966-1968(1997) [PubMed: 9395403] [Abstract]
Cited for: CLEAVAGE BY CASPASES, MUTAGENESIS.
[12]"The p53-binding protein 53BP2 also interacts with Bcl2 and impedes cell cycle progression at G2/M."
Naumovski L., Cleary M.L.
Mol. Cell. Biol. 16:3884-3892(1996) [PubMed: 8668206] [Abstract]
Cited for: INTERACTION WITH TP53BP2.
[13]"Phosphorylation of Bcl2 and regulation of apoptosis."
Ruvolo P.P., Deng X., May W.S.
Leukemia 15:515-522(2001) [PubMed: 11368354] [Abstract]
Cited for: REVIEW ON PHOSPHORYLATION.
[14]"BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M."
Yamamoto K., Ichijo H., Korsmeyer S.J.
Mol. Cell. Biol. 19:8469-8478(1999) [PubMed: 10567572] [Abstract]
Cited for: PHOSPHORYLATION BY ASK1/JNK1.
[15]"PUMA induces the rapid apoptosis of colorectal cancer cells."
Yu J., Zhang L., Hwang P.M., Kinzler K.W., Vogelstein B.
Mol. Cell 7:673-682(2001) [PubMed: 11463391] [Abstract]
Cited for: INTERACTION WITH BBC3 AND BCL2L1.
[16]"BNIPL-2, a novel homologue of BNIP-2, interacts with Bcl-2 and Cdc42GAP in apoptosis."
Qin W., Hu J., Guo M., Xu J., Li J., Yao G., Zhou X., Jiang H., Zhang P., Shen L., Wan D., Gu J.
Biochem. Biophys. Res. Commun. 308:379-385(2003) [PubMed: 12901880] [Abstract]
Cited for: INTERACTION WITH BNIPL.
[17]"The flexible loop of Bcl-2 is required for molecular interaction with immunosuppressant FK-506 binding protein 38 (FKBP38)."
Kang C.B., Tai J., Chia J., Yoon H.S.
FEBS Lett. 579:1469-1476(2005) [PubMed: 15733859] [Abstract]
Cited for: INTERACTION WITH FKBP8.
[18]"BMRP is a Bcl-2 binding protein that induces apoptosis."
Chintharlapalli S.R., Jasti M., Malladi S., Parsa K.V.L., Ballestero R.P., Gonzalez-Garcia M.
J. Cell. Biochem. 94:611-626(2005) [PubMed: 15547950] [Abstract]
Cited for: INTERACTION WITH MRPL41.
[19]"Bcl-2 localized at the nuclear compartment induces apoptosis after transient overexpression."
Portier B.P., Taglialatela G.
J. Biol. Chem. 281:40493-40502(2006) [PubMed: 17090549] [Abstract]
Cited for: INTERACTION WITH FKBP8.
[20]"Solution structure of the antiapoptotic protein bcl-2."
Petros A.M., Medek A., Nettesheim D.G., Kim D.H., Yoon H.S., Swift K., Matayoshi E.D., Oltersdorf T., Fesik S.W.
Proc. Natl. Acad. Sci. U.S.A. 98:3012-3017(2001) [PubMed: 11248023] [Abstract]
Cited for: STRUCTURE BY NMR OF 1-207.
[21]"An inhibitor of Bcl-2 family proteins induces regression of solid tumours."
Oltersdorf T., Elmore S.W., Shoemaker A.R., Armstrong R.C., Augeri D.J., Belli B.A., Bruncko M., Deckwerth T.L., Dinges J., Hajduk P.J., Joseph M.K., Kitada S., Korsmeyer S.J., Kunzer A.R., Letai A., Li C., Mitten M.J., Nettesheim D.G. expand/collapse author list , Ng S.-C., Nimmer P.M., O'Connor J.M., Oleksijew A., Petros A.M., Reed J.C., Shen W., Tahir S.K., Thompson C.B., Tomaselli K.J., Wang B., Wendt M.D., Zhang H., Fesik S.W., Rosenberg S.H.
Nature 435:677-681(2005) [PubMed: 15902208] [Abstract]
Cited for: STRUCTURE BY NMR OF 45-207.
[22]"Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL."
Bruncko M., Oost T.K., Belli B.A., Ding H., Joseph M.K., Kunzer A., Martineau D., McClellan W.J., Mitten M., Ng S.-C., Nimmer P.M., Oltersdorf T., Park C.-M., Petros A.M., Shoemaker A.R., Song X., Wang X., Wendt M.D. expand/collapse author list , Zhang H., Fesik S.W., Rosenberg S.H., Elmore S.W.
J. Med. Chem. 50:641-662(2007) [PubMed: 17256834] [Abstract]
Cited for: STRUCTURE BY NMR OF 44-207.
+Additional computationally mapped references.

Cross-references

Sequence databases

M13994 mRNA. Translation: AAA51813.1. Sequence problems.
M13995 mRNA. Translation: AAA51814.1. Sequence problems.
M14745 mRNA. Translation: AAA35591.1.
X06487 mRNA. Translation: CAA29778.1.
AY220759 Genomic DNA. Translation: AAO26045.1.
BC027258 mRNA. Translation: AAH27258.1.
S72602 Genomic DNA. Translation: AAD14111.1. Sequence problems.
IPIIPI00020961.
IPI00217817.
PIRTVHUB1. B29409.
TVHUA1. C37332.
RefSeqNP_000624.2.
UniGeneHs.150749

3D structure databases

EntryMethodResolution (Å)ChainPositionsPDBsum
1G5MNMR-A1-207[»]
1GJHNMR-A1-207[»]
1YSWNMR-A3-207[»]
2O21NMR-A3-207[»]
2O22NMR-A3-207[»]
2O2FNMR-A8-204[»]
2W3LX-ray2.10A/B9-206[»]
DisProtDP00297.
ModBaseSearch...

Protein-protein interaction databases

DIPDIP:1043N.
IntActP10415. 32 interactions.
STRINGP10415.

PTM databases

PhosphoSiteP10415.

Proteomic databases

PRIDEP10415.

Genome annotation databases

EnsemblENST00000333681; ENSP00000329623; ENSG00000171791; Homo sapiens. [Genome view]
ENST00000398117; ENSP00000381185; ENSG00000171791; Homo sapiens. [Genome view]
ENST00000444484; ENSP00000404214; ENSG00000171791; Homo sapiens. [Genome view]
GeneID596.
KEGGhsa:596.
UCSCuc002lit.1. human.
uc002liv.1. human.

Organism-specific databases

CTD596.
GeneCardsGC18M058941.
H-InvDBHIX0014496.
HGNCHGNC:990. BCL2.
HPACAB000003.
MIM151430. gene+phenotype.
Orphanet545. Follicular lymphoma.
PharmGKBPA25302.
GenAtlasSearch...

Phylogenomic databases

HOGENOMP10415.
HOVERGENP10415.
OMAGYEWEAG.

Enzyme and pathway databases

Pathway_Interaction_DBcaspase_pathway. Caspase cascade in apoptosis.
ceramidepathway. Ceramide signaling pathway.
epopathway. EPO signaling pathway.
faspathway. FAS signaling pathway (CD95).
hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.
il2_pi3kpathway. IL2 signaling events mediated by PI3K.
il2_stat5pathway. IL2 signaling events mediated by STAT5.
il2_1pathway. IL2-mediated signaling events.
nfat_3pathway. Role of Calcineurin-dependent NFAT signaling in lymphocytes.
rxr_vdr_pathway. RXR and RAR hetrodimerization with other nuclear receptor.
kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit).
ReactomeREACT_578. Apoptosis.

Gene expression databases

ArrayExpressP10415.
BgeeP10415.
CleanExHS_BCL2.
GenevestigatorP10415.
GermOnlineENSG00000171791. Homo sapiens.

Family and domain databases

InterProIPR013278. Apop_reg_Bcl2.
IPR002475. BCL2_apoptsis.
IPR000712. Bcl2_BH.
IPR003093. Bcl2_BH4.
IPR004725. Bcl2_reg.
[Graphical view]
PfamPF00452. Bcl-2. 1 hit.
PF02180. BH4. 1 hit.
[Graphical view]
PRINTSPR01863. APOPREGBCL2.
PR01862. BCL2FAMILY.
SMARTSM00337. BCL. 1 hit.
SM00265. BH4. 1 hit.
[Graphical view]
TIGRFAMsTIGR00865. bcl-2. 1 hit.
PROSITEPS50062. BCL2_FAMILY. 1 hit.
PS01080. BH1. 1 hit.
PS01258. BH2. 1 hit.
PS01259. BH3. 1 hit.
PS01260. BH4_1. 1 hit.
PS50063. BH4_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

DrugBankDB01248. Docetaxel.
DB01073. Fludarabine.
DB01065. Melatonin.
DB01229. Paclitaxel.
DB01367. Rasagiline.
NextBio2423.
PMAP-CutDBP10415.
SOURCESearch...

Entry information

Entry nameBCL2_HUMAN
AccessionPrimary (citable) accession number: P10415
Secondary accession number(s): P10416, Q13842, Q16197
Entry history
Integrated into UniProtKB/Swiss-Prot: July 1, 1989
Last sequence update: April 1, 1993
Last modified: November 3, 2009
This is version 139 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

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List of human entries with polymorphisms or disease mutations

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Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents