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7  structures 0  species 2  interactions 0  sequences 0  architectures

Family: Bcl-2_3 (PF15286)

Summary: Apoptosis regulator M11, B cell 2 leukaemia/lymphoma like

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Bcl-2 family Edit Wikipedia article

Apoptosis regulator proteins, Bcl-2 family
PDB 1maz EBI.jpg
Structure of human Bcl-xL, an inhibitor of programmed cell death.[1]
Symbol Bcl-2
Pfam PF00452
InterPro IPR000712
SCOP 1maz
OPM superfamily 42
OPM protein 2l5b
Bcl-2 homology region 4
PDB 1af3 EBI.jpg
rat bcl-xl an apoptosis inhibitory protein
Symbol BH4
Pfam PF02180
InterPro IPR003093
SCOP 1af3
TCDB 1.A.21

Apoptosis regulator Bcl-2 is a family of evolutionarily related proteins. These proteins govern mitochondrial outer membrane permeabilization (MOMP) and can be either pro-apoptotic (Bax, BAD, Bak and Bok among others) or anti-apoptotic (including Bcl-2 proper, Bcl-xL, and Bcl-w, among an assortment of others). There are a total of 25 genes in the Bcl-2 family known to date.


Overview of signal transduction pathways involved in apoptosis.

Active cell suicide (apoptosis) is induced by events such as growth factor withdrawal and toxins. It is controlled by regulators, which have either an inhibitory effect on programmed cell death (anti-apoptotic) or block the protective effect of inhibitors (pro-apoptotic).[2][3] Many viruses have found a way of countering defensive apoptosis by encoding their own anti-apoptosis genes preventing their target-cells from dying too soon.

There are a number of theories concerning how the Bcl-2 gene family exert their pro- or anti-apoptotic effect. An important one states that this is achieved by activation or inactivation of an inner mitochondrial permeability transition pore, which is involved in the regulation of matrix Ca2+, pH, and voltage. It is also thought that some Bcl-2 family proteins can induce (pro-apoptotic members) or inhibit (anti-apoptotic members) the release of cytochrome c into the cytosol which, once there, activates caspase-9 and caspase-3, leading to apoptosis. Although Zamzami et al. suggest that the release of cytochrome c is indirectly mediated by the PT pore on the inner mitochondrial membrane,[4] strong evidence suggest an earlier implication of the MAC pore on the outer membrane.[5][6]

Another theory suggests that Rho proteins play a role in Bcl-2, Mcl-1 and Bid activation. Rho inhibition reduces the expression of anti-apoptotic Bcl-2 and Mcl-1 proteins and increases protein levels of pro-apoptotic Bid but had no effect on Bax or FLIP levels. Rho inhibition induces caspase-9 and caspase-3-dependent apoptosis of cultured human endothelial cells.[7]

Site of action

The site of action for the Bcl-2 family is mostly on the outer mitochondrial membrane. Within the mitochondria are apoptogenic factors (cytochrome c, Smac/Diablo homolog, Omi) that if released activate the executioners of apoptosis, the caspases.[8] Depending on their function, once activated, Bcl-2 proteins either promote the release of these factors, or keep them sequestered in the mitochondria. Whereas the activated pro-apoptotic Bak and/or Bax would form MAC and mediate the release of cytochrome c, the anti-apoptotic Bcl-2 would block it, possibly through inhibition of Bax and/or Bak.[9]


Fig: D. Domains of the Bcl-2 family[10]

The Bcl-2 family has a general structure that consists of a hydrophobic helix surrounded by amphipathic helices. Many members of the family have transmembrane domains.


The members of the Bcl-2 family share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4) (see the figure D on the left). The BH domains are known to be crucial for function, as deletion of these domains via molecular cloning affects survival/apoptosis rates. The anti-apoptotic Bcl-2 proteins, such as Bcl-2 and Bcl-xL, conserve all four BH domains. The BH domains also serve to subdivide the pro-apoptotic Bcl-2 proteins into those with several BH domains (e.g. Bax and Bak) or those proteins that have only the BH3 domain (e.g. Bim Bid, and BAD).

All proteins belonging to the Bcl-2 family[11] contain either a BH1, BH2, BH3 or BH4 domain. All anti-apoptotic proteins contain BH1 and BH2 domains, some of them contain an additional N-terminal BH4 domain (Bcl-2, Bcl-x(L), Bcl-w), which is also seen in some pro-apoptotic proteins like Bcl-x(S), Diva, Bok-L and Bok-S. On the other hand, all pro-apoptotic proteins contain a BH3 domain necessary for dimerization with other proteins of Bcl-2 family and crucial for their killing activity, some of them also contain BH1 and BH2 domains (Bax, Bak). The BH3 domain is also present in some anti-apoptotic protein, such as Bcl-2 or Bcl-x(L).

BH3-only family

The BH3-only subset of the Bcl-2 family of proteins contain only a single BH3-domain. The BH3-only members play a key role in promoting apoptosis. The BH3-only family members are Bim, Bid, BAD and others. Various apoptotic stimuli induce expression and/or activation of specific BH3-only family members, which translocate to the mitochondria and initiate Bax/Bak-dependent apoptosis.[12]


Proteins that are known to contain these domains include vertebrate Bcl-2 (alpha and beta isoforms) and Bcl-x (isoforms Bcl-x(L) and Bcl-x(S)); mammalian proteins Bax and Bak; mouse protein Bid; Xenopus laevis proteins Xr1 and Xr11; human induced myeloid leukemia cell differentiation protein MCL1 and Caenorhabditis elegans protein ced-9.

Human genes encoding proteins that belong to this family include:

See also


  1. ^ Muchmore SW, Sattler M, Liang H; et al. (May 1996). "X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death". Nature 381 (6580): 335–41. doi:10.1038/381335a0. PMID 8692274. 
  2. ^ Vaux DL (1993). "A boom time for necrobiology". Curr. Biol. 3 (12): 877–878. doi:10.1016/0960-9822(93)90223-B. PMID 15335822. 
  3. ^ Milliman CL, Korsmeyer SJ, Wang K, Yin XM, Chao DT (1996). "BID: a novel BH3 domain-only death agonist". Genes Dev. 10 (22): 2859–2869. doi:10.1101/gad.10.22.2859. PMID 8918887. 
  4. ^ Zamzami N, Brenner C, Marzo I, Susin SA, Kroemer G (April 1998). "Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins". Oncogene 16 (17): 2265–82. doi:10.1038/sj.onc.1201989. PMID 9619836. 
  5. ^ Kinnally KW, Antonsson B (May 2007). "A tale of two mitochondrial channels, MAC and PTP, in apoptosis". Apoptosis 12 (5): 857–68. doi:10.1007/s10495-007-0722-z. PMID 17294079. 
  6. ^ Martinez-Caballero S, Dejean LM, Jonas EA, Kinnally KW (June 2005). "The role of the mitochondrial apoptosis induced channel MAC in cytochrome c release". J. Bioenerg. Biomembr. 37 (3): 155–64. doi:10.1007/s10863-005-6570-z. PMID 16167172. 
  7. ^ Hippenstiel S, Schmeck B, N'Guessan PD, Seybold J, Krüll M, Preissner K, Eichel-Streiber CV, Suttorp N (October 2002). "Rho protein inactivation induced apoptosis of cultured human endothelial cells". Am. J. Physiol. Lung Cell Mol. Physiol. 283 (4): L830–8. doi:10.1152/ajplung.00467.2001. PMID 12225960. 
  8. ^ Fesik SW, Shi Y. (2001). "Controlling the caspases". Science 294 (5546): 1477–1478. doi:10.1126/science.1062236. PMID 11711663. 
  9. ^ Dejean LM, Martinez-Caballero S, Manon S, Kinnally KW (February 2006). "Regulation of the mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins". Biochim. Biophys. Acta 1762 (2): 191–201. doi:10.1016/j.bbadis.2005.07.002. PMID 16055309. 
  10. ^ Chao DT, Korsmeyer SJ (1998). "BCL-2 family: regulators of cell death". Annu. Rev. Immunol. 16: 395–419. doi:10.1146/annurev.immunol.16.1.395. PMID 9597135. 
  11. ^ Reed JC, Zha H, Aime-Sempe C, Takayama S, Wang HG (1996). "Structure-function analysis of Bcl-2 family proteins. Regulators of programmed cell death". Adv. Exp. Med. Biol. 406: 99–112. doi:10.1007/978-1-4899-0274-0_10. PMID 8910675. 
  12. ^ Michael Kastan; Abeloff, Martin D.; Armitage, James O.; Niederhuber, John E. (2008). Abeloff's clinical oncology (4th ed.). Philadelphia: Churchill Livingstone/Elsevier. ISBN 0-443-06694-9. 

This article incorporates text from the public domain Pfam and InterPro IPR000712

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Apoptosis regulator M11, B cell 2 leukaemia/lymphoma like Provide feedback

PF02180. Bcl-2_3 is a small family of eukaryotic proteins associated with autophagy. The family is found in association with PF00452.

Literature references

  1. Cruz-Reyes J, Tata JR;, Gene. 1995;158:171-179.: Cloning, characterization and expression of two Xenopus bcl-2-like cell-survival genes. PUBMED:7607538 EPMC:7607538

  2. Ku B, Woo JS, Liang C, Lee KH, Hong HS, E X, Kim KS, Jung JU, Oh BH;, PLoS Pathog. 2008;4:e25.: Structural and biochemical bases for the inhibition of autophagy and apoptosis by viral BCL-2 of murine gamma-herpesvirus 68. PUBMED:18248095 EPMC:18248095

Internal database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR029450

Some herpesviruses encode homologues of the antiapoptotic, cellular Bcl-2 to promote viral replication and pathogenesis. Members of this small group of viral proteins are homologues of Bcl-2 and seem to inhibit autophagy through binding to autophagy effector Beclin1 [PUBMED:18797192].

Domain organisation

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Pfam Clan

This family is a member of clan BCLiA (CL0551), which has the following description:

This superfamily is characterised by families of proteins that inhibit apoptosis, They are regulated by all BH3-only proteins to promote apoptosis.

The clan contains the following 5 members:

APG6 Atg14 Bcl-2 Bcl-2_3 BID


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Seed source: Jackhmmer:P89884
Previous IDs: none
Type: Family
Author: Coggill P
Number in seed: 3
Number in full: 0
Average length of the domain: 0.00 aa
Average identity of full alignment: 0 %
Average coverage of the sequence by the domain: 0.00 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 25.3 25.3
Noise cut-off 24.7 24.5
Model length: 126
Family (HMM) version: 3
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Species distribution

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Archea Archea Eukaryota Eukaryota
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Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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BH3 Bcl-2_3


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Bcl-2_3 domain has been found. There are 7 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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