Bcl-2 family

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Apoptosis regulator proteins, Bcl-2 family
PDB 1maz EBI.jpg
Structure of human Bcl-xL, an inhibitor of programmed cell death. [1]
Identifiers
SymbolBcl-2
Pfam PF00452
InterPro IPR002475
SMART SM00337
PROSITE PDOC00829
SCOP2 1maz / SCOPe / SUPFAM
OPM superfamily 40
OPM protein 2l5b
Membranome 232
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

The Bcl-2 family (TC# 1.A.21) consists of a number of evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion. [2] The Bcl-2 family proteins consists of members that either promote or inhibit apoptosis, and control apoptosis by governing mitochondrial outer membrane permeabilization (MOMP), which is a key step in the intrinsic pathway of apoptosis. A total of 25 genes in the Bcl-2 family were identified by 2008.

Contents

Members of the BCL-2 family regulate apoptosis in mammals, reptiles, amphibs, fish, and other phyla of metazoan life, with exception of nematodes and insects. [3] Their molecular structure and function, as well as their protein dynamics, are highly conserved over hundreds of millions of years in tissue forming life forms. [4]

Structure

Domains of the Bcl-2 family Bcl-2 Family.jpg
Domains of the Bcl-2 family

Bcl-2 family proteins have a general structure that consists of a hydrophobic α-helix surrounded by amphipathic α-helices. Some members of the family have transmembrane domains at their c-terminus which primarily function to localize them to the mitochondrion.

Bcl-x(L) is 233 amino acyl residues (aas) long and exhibits a single very hydrophobic putative transmembrane α-helical segment (residues 210-226) when in the membrane. Homologues of Bcl-x include the Bax (rat; 192 aas) and Bak (mouse; 208 aas) proteins, which also influence apoptosis. The high resolution structure of the monomeric soluble form of human Bcl-x(L) has been determined by both x-ray crystallography and NMR. [6]

The structure consists of two central primarily hydrophobic α-helices surrounded by amphipathic helices. The arrangement of the α-helices in Bcl-X(L) resembles that for diphtheria toxin and the colicins. Diphtheria toxin forms a transmembrane pore and translocates the toxic catalytic domain into the animal cell cytoplasm. The colicins similarly form pores in lipid bilayers. Structural homology therefore suggests that Bcl-2 family members that contain the BH1 and BH2 domains (Bcl-X(L) Bcl-2 and Bax) function similarly.

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 figure). 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 [7] 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) and 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 and Bak). The BH3 domain is also present in some anti-apoptotic protein, such as Bcl-2 or Bcl-x(L). The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3) are in close spatial proximity. They form an elongated cleft that may provide the binding site for other Bcl-2 family members.

Function

Overview of signal transduction pathways involved in apoptosis. Signal transduction pathways.svg
Overview of signal transduction pathways involved in apoptosis.

Regulated cell death (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). [8] [9] 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.

Bcl-x is a dominant regulator of programmed cell death in mammalian cells. [10] [11] The long form (Bcl-x(L), displays cell death repressor activity, but the short isoform (Bcl-x(S)) and the β-isoform (Bcl-xβ) promote cell death. Bcl-x(L), Bcl-x(S) and Bcl-xβ are three isoforms derived by alternative RNA splicing.

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, [12] strong evidence suggest an earlier implication of the MAC pore on the outer membrane. [13] [14]

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. [15]

Site of action

These proteins are localized to the outer mitochondrial membrane of the animal cell where they are thought to form a complex with the voltage-dependent anion channel porin (VDAC). Interaction of Bcl-2 with VDAC1 or with peptides derived from VDAC3 protects against cell death by inhibiting cytochrome c release. A direct interaction of Bcl-2 with bilayer-reconstituted purified VDAC was demonstrated, with Bcl-2 decreasing channel conductance. [16]

Within the mitochondria are apoptogenic factors (cytochrome c, Smac/Diablo homolog, Omi) that if released activate the executioners of apoptosis, the caspases. [17] 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. [18]

Proteins of the Bcl-2 family are also present in the perinuclear envelope and are widely distributed in many body tissues. Their ability to form oligomeric pores in artificial lipid bilayers has been documented but the physiological significance of pore formation is not clear. Each of these proteins has distinctive properties, including some degree of ion selectivity. [19]

Transport reaction

The generalized transport reaction proposed for membrane-embedded, oligomeric Bcl-2 family members is:

cytochrome c (mitochondrial intermembrane space) ⇌ cytochrome c (cytoplasm)

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. [20]

Examples

Proteins that are known to contain these domains include vertebrate Bcl-2 (alpha and beta isoforms) and Bcl-x (isoforms Bcl-x(L).

See also

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Type of programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses 50 to 70 billion cells each day due to apoptosis. For the average human child between 8 and 14 years old, each day the approximate loss is 20 to 30 billion cells.

<span class="mw-page-title-main">Bcl-2</span> Protein found in humans

Bcl-2, encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can either inhibit or induce it. It was the first apoptosis regulator identified in any organism.

<span class="mw-page-title-main">Apoptosome</span> A protein complex involved in the cellular apoptotic process.

The apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal (intrinsic) or external (extrinsic) cell death stimulus. Stimuli can vary from DNA damage and viral infection to developmental cues such as those leading to the degradation of a tadpole's tail.

<span class="mw-page-title-main">Apoptosis regulator BAX</span> Mammalian protein found in Homo sapiens

Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the BAX gene. BAX is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

p53 upregulated modulator of apoptosis Protein-coding gene in the species Homo sapiens

The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family. In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene. The expression of PUMA is regulated by the tumor suppressor p53. PUMA is involved in p53-dependent and -independent apoptosis induced by a variety of signals, and is regulated by transcription factors, not by post-translational modifications. After activation, PUMA interacts with antiapoptotic Bcl-2 family members, thus freeing Bax and/or Bak which are then able to signal apoptosis to the mitochondria. Following mitochondrial dysfunction, the caspase cascade is activated ultimately leading to cell death.

<span class="mw-page-title-main">Phorbol-12-myristate-13-acetate-induced protein 1</span> Protein-coding gene in the species Homo sapiens

Phorbol-12-myristate-13-acetate-induced protein 1 is a protein that in humans is encoded by the PMAIP1 gene, and is also known as Noxa.

<span class="mw-page-title-main">Bcl-2 homologous antagonist killer</span> Protein-coding gene in the species Homo sapiens

Bcl-2 homologous antagonist/killer is a protein which in humans is encoded by the BAK1 gene on chromosome 6. It belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress.

<span class="mw-page-title-main">Bcl-2-associated death promoter</span> Mammalian protein found in Homo sapiens

The BCL2 associated agonist of cell death (BAD) protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family, a subfamily of the Bcl-2 family. It does not contain a C-terminal transmembrane domain for outer mitochondrial membrane and nuclear envelope targeting, unlike most other members of the Bcl-2 family. After activation, it is able to form a heterodimer with anti-apoptotic proteins and prevent them from stopping apoptosis.

<span class="mw-page-title-main">Bcl-xL</span> Transmembrane molecule in the mitochondria

B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondrial contents such as cytochrome c, which leads to caspase activation and ultimately, programmed cell death.

Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

<span class="mw-page-title-main">Bcl-2-like protein 1</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 1 is a protein encoded in humans by the BCL2L1 gene. Through alternative splicing, the gene encodes both of the human proteins Bcl-xL and Bcl-xS.

<span class="mw-page-title-main">BCL2L11</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 11, commonly called BIM, is a protein that in humans is encoded by the BCL2L11 gene.

<span class="mw-page-title-main">Diablo homolog</span> Protein-coding gene in the species Homo sapiens

Diablo homolog (DIABLO) is a mitochondrial protein that in humans is encoded by the DIABLO gene on chromosome 12. DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC. This protein binds inhibitor of apoptosis proteins (IAPs), thus freeing caspases to activate apoptosis. Due to its proapoptotic function, SMAC is implicated in a broad spectrum of tumors, and small molecule SMAC mimetics have been developed to enhance current cancer treatments.

<span class="mw-page-title-main">Bcl-2-interacting killer</span> Protein-coding gene in the species Homo sapiens

Bcl-2-interacting killer is a protein that in humans is encoded by the BIK gene.

<span class="mw-page-title-main">HRK (gene)</span>

Activator of apoptosis harakiri is a protein that in humans is encoded by the HRK gene.

<span class="mw-page-title-main">Mitochondrial apoptosis-induced channel</span>

The mitochondrial apoptosis-induced channel, is an early marker of the onset of apoptosis. This ion channel is formed on the outer mitochondrial membrane in response to certain apoptotic stimuli. MAC activity is detected by patch clamping mitochondria from apoptotic cells at the time of cytochrome c release.

<span class="mw-page-title-main">BOK (gene)</span> Protein-coding gene in the species Homo sapiens

Bok is a protein-coding gene of the Bcl-2 family that is found in many invertebrates and vertebrates. It induces apoptosis, a special type of cell death. Currently, the precise function of Bok in this process is unknown.

<span class="mw-page-title-main">BCL2L10</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 10 is a protein that in humans is encoded by the BCL2L10 gene.

Cell death abnormality gene 9 (CED-9), also known as apoptosis regulator CED-9, is a gene found in Caenorhabditis elegans that inhibits/represses programmed cell death (apoptosis). The gene was discovered while searching for mutations in the apoptotic pathway after the discovery of the apoptosis promoting genes CED-3 and CED-4. The gene gives rise to the apoptosis regulator CED-9 protein found as an Integral membrane protein in the mitochondrial membrane. The protein is homologous to the human apoptotic regulator Bcl-2 as well as all other proteins in the Bcl-2 protein family. CED-9 is involved in the inhibition of CED-4 which is the activator of the CED-3 caspase. Because of the pathway homology with humans as well as the specific protein homology, CED-9 has been used to represent the human cell apoptosis interactions of Bcl-2 in research.

References

  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. Bibcode:1996Natur.381..335M. doi:10.1038/381335a0. hdl: 10220/8302 . PMID   8692274. S2CID   4279148.
  2. ↑ Youle, Richard J.; Strasser, Andreas (2008). "The BCL-2 protein family: opposing activities that mediate cell death". Nature Reviews Molecular Cell Biology. 9 (1): 47–59. doi:10.1038/nrm2308. PMID   18097445. S2CID   7033834.
  3. ↑ Banjara, Suresh; Suraweera, Chathura D.; Hinds, Mark G.; Kvansakul, Marc (12 January 2020). "The Bcl-2 Family: Ancient Origins, Conserved Structures, and Divergent Mechanisms". Biomolecules. 10 (1): 128. doi: 10.3390/biom10010128 . PMC   7022251 . PMID   31940915.
  4. ↑ Heckmeier, Philipp J.; Ruf, Jeannette; Rochereau, Charlotte; Hamm, Peter (February 27, 2024). "A billion years of evolution manifest in nanosecond protein dynamics". Proceedings of the National Academy of Sciences. 121 (10). arXiv: 2309.06298 . doi:10.1073/pnas.2318743121. PMID   38412135.
  5. ↑ 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.
  6. ↑ Muchmore, S. W.; Sattler, M.; Liang, H.; Meadows, R. P.; Harlan, J. E.; Yoon, H. S.; Nettesheim, D.; Chang, B. S.; Thompson, C. B. (1996-05-23). "X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death". Nature. 381 (6580): 335–341. Bibcode:1996Natur.381..335M. doi:10.1038/381335a0. hdl: 10220/8302 . ISSN   0028-0836. PMID   8692274. S2CID   4279148.
  7. ↑ Reed JC, Zha H, Aime-Sempe C, Takayama S, Wang HG (1996). "Structure—Function Analysis of BCL-2 Family Proteins". Mechanisms of Lymphocyte Activation and Immune Regulation VI. Advances in Experimental Medicine and Biology. Vol. 406. pp. 99–112. doi:10.1007/978-1-4899-0274-0_10. ISBN   978-1-4899-0276-4. PMID   8910675.
  8. ↑ Vaux DL (1993). "A boom time for necrobiology". Curr. Biol. 3 (12): 877–878. Bibcode:1993CBio....3..877V. doi:10.1016/0960-9822(93)90223-B. PMID   15335822. S2CID   9638716.
  9. ↑ 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.
  10. ↑ Boise, L. H.; González-García, M.; Postema, C. E.; Ding, L.; Lindsten, T.; Turka, L. A.; Mao, X.; Nuñez, G.; Thompson, C. B. (1993-08-27). "bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death" (PDF). Cell. 74 (4): 597–608. doi:10.1016/0092-8674(93)90508-n. hdl: 2027.42/30629 . ISSN   0092-8674. PMID   8358789. S2CID   13542617.
  11. ↑ Tsujimoto, Y.; Shimizu, S. (2000-01-21). "Bcl-2 family: life-or-death switch". FEBS Letters. 466 (1): 6–10. doi: 10.1016/s0014-5793(99)01761-5 . ISSN   0014-5793. PMID   10648802. S2CID   29229869.
  12. ↑ 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. S2CID   18517302.
  13. ↑ 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.
  14. ↑ 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. S2CID   27152003.
  15. ↑ 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. S2CID   7033902.
  16. ↑ Arbel, Nir; Shoshan-Barmatz, Varda (2010-02-26). "Voltage-dependent anion channel 1-based peptides interact with Bcl-2 to prevent antiapoptotic activity". The Journal of Biological Chemistry. 285 (9): 6053–6062. doi: 10.1074/jbc.M109.082990 . ISSN   1083-351X. PMC   2825399 . PMID   20037155.
  17. ↑ Fesik SW, Shi Y (2001). "Controlling the caspases". Science. 294 (5546): 1477–1478. doi:10.1126/science.1062236. PMID   11711663. S2CID   11392850.
  18. ↑ 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.
  19. ↑ Antonsson, B.; Montessuit, S.; Lauper, S.; Eskes, R.; Martinou, J. C. (2000-01-15). "Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria". The Biochemical Journal. 345 (2): 271–278. doi:10.1042/0264-6021:3450271. ISSN   0264-6021. PMC   1220756 . PMID   10620504.
  20. ↑ Michael Kastan; Abeloff, Martin D.; Armitage, James O.; Niederhuber, John E. (2008). Abeloff's clinical oncology (4th ed.). Philadelphia: Churchill Livingstone/Elsevier. ISBN   978-0-443-06694-8.
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