Summary: Bcl-2 homology region 4
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Bcl-2 family Edit Wikipedia article
|Apoptosis regulator proteins, Bcl-2 family|
Structure of human Bcl-xL, an inhibitor of programmed cell death.
|Bcl-2 homology region 4|
rat bcl-xl an apoptosis inhibitory protein
Apoptosis regulator Bcl-2, BH 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.
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). 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, strong evidence suggest an earlier implication of the MAC pore on the outer membrane.
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.
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 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. Bid, Bim and Bad). 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 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. 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.
All proteins belonging to the Bcl-2 family 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 never seen in pro-apoptotic proteins, except for Bcl-x(S). On the other hand, all pro-apoptotic proteins contain a BH3 domain (except for Bad) 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
BH3-only family of proteins includes those of the Bcl-2 family proteins, which contain only a single BH-domain. The BH3-only family members play a key role in promoting apoptosis. The BH3-only family members are BAD, Bim 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.
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
- Bcl-2 inhibitor, anti-cancer drugs targeted at this family of proteins
- 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.
- Vaux DL (1993). "A boom time for necrobiology". Curr. Biol. 3 (12): 877–878. doi:10.1016/0960-9822(93)90223-B. PMID 15335822.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Fesik SW, Shi Y. (2001). "Controlling the caspases". Science 294 (5546): 1477–1478. doi:10.1126/science.1062236. PMID 11711663.
- 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.
- 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. PMID 8910675.
- 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.
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Bcl-2 homology region 4 Provide feedback
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This tab holds annotation information from the InterPro database.
InterPro entry IPR003093
Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans [PUBMED:11341280]. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.
Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes [PUBMED:12631689]. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.
Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 [PUBMED:9735050]. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily [PUBMED:9735050]. Full-length Bcl-2 proteins feature all four BH domains, seven alpha-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope.
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) [PUBMED:15335822, PUBMED:8918887]. 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.
All proteins belonging to the Bcl-2 family [PUBMED:8910675] 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 never seen in pro-apoptotic proteins, except for Bcl-x(S). On the other hand, all pro-apoptotic proteins contain a BH3 domain (except for Bad) necessary for dimerisation 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). 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.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Biological process||regulation of apoptotic process (GO:0042981)|
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|Seed source:||Alignment kindly provided by SMART|
|Number in seed:||11|
|Number in full:||223|
|Average length of the domain:||25.40 aa|
|Average identity of full alignment:||54 %|
|Average coverage of the sequence by the domain:||12.65 %|
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build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||12|
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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 BH4 domain has been found. There are 92 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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