BH3 interacting domain death agonist
Encyclopedia
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 domain
s of homology
entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4), 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.
, Bax
, leading to the insertion of Bax into organelle
membranes, primarily the outer mitochondrial membrane. Bax is believed to interact with, and induce the opening of the mitochondrial voltage-dependent anion channel, VDAC
. Alternatively, growing evidence suggest that activated Bax and/or Bak
form an oligomeric pore, MAC in the outer membrane. This results in the release of cytochrome c and other pro-apoptotic factors (such as SMAC
/DIABLO) from the mitochondria, often referred to as mitochondrial outer membrane permeabilization, leading to activation of caspases. This defines BID as a direct activator of Bax, a role common to some of the pro-apoptotic Bcl-2 proteins containing only the BH3 domain.
The anti-apoptotic Bcl-2 proteins, including Bcl-2 itself, can bind BID and inhibit BID's ability to activate Bax. As a result, the anti-apoptotic Bcl-2 proteins may inhibit apoptosis by sequestering BID, leading to reduced Bax activation.
The expression of BID is upregulated by the tumor suppressor
p53
, and BID has been shown to be involved in p53-mediated apoptosis. The p53 protein is a transcription factor
that, when activated as part of the cell's response to stress, regulates many downstream target genes, including BID. However, p53 also has a transcription-independent role in apoptosis. In particular, p53 interacts with Bax
, promoting Bax activation and the insertion of Bax into the mitochondrial membrane.
The BH3 interacting-domain death agonist has been shown to interact
with Bcl-2
, MCL1
, Caspase 8
and Caspase 2
.
Several reports have demonstrated that caspase
-8, and its substrate BID, are frequently activated in response to certain apoptotic stimuli in a death receptor-independent manner. N-hydroxy-L-arginine (NOHA), a stable intermediate product formed during the conversion of L-arginine to nitric oxide
activates caspase-8. Activation of caspase-8, and subsequent BID cleavage participate in cytochrome-c mediated apoptosis
. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mediated activation of caspase-9 via cytochrome-c release has been shown to result in the activation of caspase-8 and Bid cleavage. Aspirin
and Curcumin
(diferuloylmethane) too activate caspase-8 to cleave and translocated Bid, induced a conformational change in and translocation of Bax and cytochrome-c release.
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is a pro-apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
member of the Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
protein family. Bcl-2 family members share one or more of the four characteristic domain
Domain (biology)
In biological taxonomy, a domain is the highest taxonomic rank of organisms, higher than a kingdom. According to the three-domain system of Carl Woese, introduced in 1990, the Tree of Life consists of three domains: Archaea, Bacteria and Eukarya...
s of homology
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4), and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
regulators that are involved in a wide variety of cellular activities.
Interactions
BID is a pro-apoptotic Bcl-2 protein containing only the BH3 domain. In response to apoptotic signaling, BID interacts with another Bcl-2 family proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, Bax
Bcl-2-associated X protein
The Bcl-2–associated X protein, or Bax is a protein of the Bcl-2 gene family. It promotes apoptosis by competing with Bcl-2 proper.The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family....
, leading to the insertion of Bax into organelle
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
membranes, primarily the outer mitochondrial membrane. Bax is believed to interact with, and induce the opening of the mitochondrial voltage-dependent anion channel, VDAC
Voltage-dependent anion channel
Voltage-dependent anion channels are a class of porin ion channel located on the outer mitochondrial membrane.This major protein of the outer mitochondrial membrane of eukaryotes. It forms a voltage-dependent anion-selective channel that behaves as a general diffusion pore for small hydrophilic...
. Alternatively, growing evidence suggest that activated Bax and/or Bak
Bcl-2 homologous antagonist killer
Bcl-2 homologous antagonist/killer is a protein that in humans is encoded by the BAK1 gene. BAK1 orthologs have been identified in most mammals for which complete genome data are available....
form an oligomeric pore, MAC in the outer membrane. This results in the release of cytochrome c and other pro-apoptotic factors (such as SMAC
Diablo homolog
Diablo homolog, mitochondrial is a protein that in humans is encoded by the DIABLO gene . DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC.- Function :...
/DIABLO) from the mitochondria, often referred to as mitochondrial outer membrane permeabilization, leading to activation of caspases. This defines BID as a direct activator of Bax, a role common to some of the pro-apoptotic Bcl-2 proteins containing only the BH3 domain.
The anti-apoptotic Bcl-2 proteins, including Bcl-2 itself, can bind BID and inhibit BID's ability to activate Bax. As a result, the anti-apoptotic Bcl-2 proteins may inhibit apoptosis by sequestering BID, leading to reduced Bax activation.
The expression of BID is upregulated by the tumor suppressor
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, and BID has been shown to be involved in p53-mediated apoptosis. The p53 protein is a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
that, when activated as part of the cell's response to stress, regulates many downstream target genes, including BID. However, p53 also has a transcription-independent role in apoptosis. In particular, p53 interacts with Bax
Bcl-2-associated X protein
The Bcl-2–associated X protein, or Bax is a protein of the Bcl-2 gene family. It promotes apoptosis by competing with Bcl-2 proper.The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family....
, promoting Bax activation and the insertion of Bax into the mitochondrial membrane.
The BH3 interacting-domain death agonist has been shown to interact
Protein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
, MCL1
MCL1
Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the MCL1 gene.- Function :The protein encoded by this gene belongs to the Bcl-2 family. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been...
, Caspase 8
Caspase 8
Caspase 8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase 3.CASP8 orthologs have been identified in numerous mammals for which complete genome data are available...
and Caspase 2
Caspase 2
Caspase 2 also known as CASP2 is an enzyme that, in humans, is encoded by the CASP2 gene. CASP2 orthologs have been identified in nearly all mammals for which complete genome data are available...
.
Cleavage
Caspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
-8, and its substrate BID, are frequently activated in response to certain apoptotic stimuli in a death receptor-independent manner. N-hydroxy-L-arginine (NOHA), a stable intermediate product formed during the conversion of L-arginine to nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
activates caspase-8. Activation of caspase-8, and subsequent BID cleavage participate in cytochrome-c mediated apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mediated activation of caspase-9 via cytochrome-c release has been shown to result in the activation of caspase-8 and Bid cleavage. Aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
and Curcumin
Curcumin
Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family . The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenols and are responsible for the yellow color of turmeric...
(diferuloylmethane) too activate caspase-8 to cleave and translocated Bid, induced a conformational change in and translocation of Bax and cytochrome-c release.
See also
- ApoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
- ApoptosomeApoptosomeThe 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 or external cell death stimulus...
- Bcl-2Bcl-2Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
- Bcl-2-associated X proteinBcl-2-associated X proteinThe Bcl-2–associated X protein, or Bax is a protein of the Bcl-2 gene family. It promotes apoptosis by competing with Bcl-2 proper.The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family....
(BAX) - Caspases
- The Proteolysis MapThe Proteolysis MapThe Proteolysis MAP is an integrated web resource focused on proteases.-Rationale:PMAP is to aid the protease researchers in reasoning about proteolytic networks and metabolic pathways.-History and funding:...
- Cytochrome cCytochrome cThe Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
- NoxaNoxaPhorbol-12-myristate-13-acetate-induced protein 1 is a protein that in humans is encoded by the PMAIP1 gene.Noxa is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members can form hetero- or homodimers, and they act as anti- or pro-apoptotic regulators that are involved in a wide...
- MitochondrionMitochondrionIn cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
- p53 upregulated modulator of apoptosisP53 upregulated modulator of apoptosisThe p53 upregulated modulator of apoptosis also known as Bcl-2-binding component 3 , 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....
(PUMA)