Reviewed, UniProtKB/Swiss-Prot P10415 (BCL2_HUMAN)

Names and origin

Protein names

Recommended name:
    Apoptosis regulator Bcl-2

Gene names

Name:

BCL2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	239 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence 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.
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.
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 process	Apoptosis
Cellular component	Endoplasmic reticulum Membrane Mitochondrion Mitochondrion outer membrane Nucleus
Coding sequence diversity	Alternative splicing Chromosomal rearrangement Polymorphism
Disease	Disease mutation Proto-oncogene
Domain	Transmembrane
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	B 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 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 regulation of mitochondrial membrane permeability 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 radiation Non-traceable author statement. Source: UniProtKB response to toxin Inferred from direct assay. Source: HGNC
Cellular component	endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW mitochondrial outer membrane Inferred from direct assay. Source: UniProtKB nuclear membrane Inferred from direct assay. Source: UniProtKB
Molecular function	BH3 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...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		1	EBI-77694,EBI-77694
BAD	Q92934	3	EBI-77694,EBI-700771
Bad	Q61337	3	EBI-77694,EBI-400328	From a different organism.
BAK1	Q16611	1	EBI-77694,EBI-519866
BAX	Q07812	2	EBI-77694,EBI-516580
Bax	Q07813	1	EBI-77694,EBI-700711	From a different organism.
BBC3	Q9BXH1	3	EBI-77694,EBI-519884
BBC3	Q9BXH1-1	1	EBI-77694,EBI-519891
BBC3	Q9BXH1-2	1	EBI-77694,EBI-519896
BCAP31	P51572	2	EBI-77694,EBI-77683
BCL2L11	O43521	1	EBI-77694,EBI-526406
BCL2L11	O43521-1	1	EBI-77694,EBI-526416
BCL2L11	O43521-2	2	EBI-77694,EBI-526420
Bcl2l11	O54918	1	EBI-77694,EBI-526067	From a different organism.
BID	P55957	3	EBI-77694,EBI-519672
BIK	Q13323	2	EBI-77694,EBI-700794
bim-alpha1	Q8WYM1	1	EBI-77694,EBI-1002160
Bmf	Q91ZE9	2	EBI-77694,EBI-708032	From a different organism.
BNIP3L	O60238	1	EBI-77694,EBI-849893
NLRP1	Q9C000	5	EBI-77694,EBI-1220518
PPP1CA	P62136	1	EBI-77694,EBI-357253
PPP1CB	P62140	1	EBI-77694,EBI-352350
PPP1CC	P36873-1	1	EBI-77694,EBI-356289
SIVA1	O15304	1	EBI-77694,EBI-520756
SPNS1	Q9H2V7	1	EBI-77694,EBI-1386527

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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 239

239

Apoptosis regulator Bcl-2

PRO_0000143048

Regions

Transmembrane

212 – 233

22

Potential

Motif

10 – 30

21

BH4

Motif

93 – 107

15

BH3

Motif

136 – 155

20

BH1

Motif

187 – 202

16

BH2

Sites

Site

34 – 35

2

Cleavage; by caspase-3

Amino acid modifications

Modified residue

70

1

Phosphoserine; by PKC By similarity

Natural variations

Alternative sequence

196 – 239

44

DAFVE…YLGHK → VGASGDVS in isoform Beta.

VSP_000512

Natural variant

7

1

T → S

VAR_000827

Natural variant

43

1

A → T: dbSNP rs1800477.

VAR_014716

Natural variant

59

1

P → S in non-Hodgkin lymphoma; somatic mutation.

VAR_000828

Natural variant

93

1

V → I in non-Hodgkin lymphoma; somatic mutation.

VAR_000829

Experimental info

Mutagenesis

34

1

D → A: Abolishes cleavage by caspase-3

Mutagenesis

64

1

D → A: No effect on cleavage by caspase-3

Mutagenesis

145

1

G → A: No heterodimerization with BAX and loss of anti-apoptotic activity

Mutagenesis

188

1

W → A: No heterodimerization with BAX and loss of anti-apoptotic activity

Sequence conflict

48

1

I → F in CAA29778. Ref.4

Sequence conflict

59

1

P → T in AAA35591. Ref.3

Sequence conflict

117

1

S → R in AAA35591. Ref.3

Sequence conflict

129

1

R → C mRNA Ref.4 Ref.6

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

239

Helix Strand Turn

Details...

Helix

52 – 65

14

Turn

73 – 75

3

Beta strand

88 – 92

5

Helix

93 – 108

16

Beta strand

110 – 112

3

Helix

114 – 117

4

Helix

123 – 137

15

Helix

144 – 163

20

Helix

167 – 183

17

Helix

185 – 192

8

Helix

195 – 202

8

Sequences

	Sequence		Length	Mass (Da)
	Isoform Alpha [UniParc]. Last modified April 1, 1993. Version 2. Checksum: 3C49F2B714DC9CCB	FASTA	239	26,266
	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
	Isoform Beta [UniParc]. Checksum: 2A271F901814EF69		203	22,141
	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 LNRHLHTWIQ DNGGWVGASG DVS

References

	« Hide 'large scale' referencesShow '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).
[5]	"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." Rieder M.J., Livingston R.J., Daniels M.R., Montoya M.A., Chung M.-W., Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D., Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A. Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT THR-43.
[6]	"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.
[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. , 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. , 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.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Wikipedia

Bcl-2 entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

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.

PIR

TVHUB1. B29409.
TVHUA1. C37332.

RefSeq

NP_000624.2.

UniGene

Hs.150749

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1G5M	NMR	-	A	1-207	[»]
1GJH	NMR	-	A	1-207	[»]
1YSW	NMR	-	A	45-207	[»]
2O21	NMR	-	A	44-207	[»]
2O22	NMR	-	A	44-207	[»]
2O2F	NMR	-	A	8-31	[»]
			A	92-204	[»]

DisProt

DP00297.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:1043N.

IntAct

P10415.

PTM databases