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5  structures 36  species 0  interactions 65  sequences 2  architectures

Family: BID (PF06393)

Summary: BH3 interacting domain (BID)

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This is the Wikipedia entry entitled "BH3 interacting-domain death agonist". More...

BH3 interacting-domain death agonist Edit Wikipedia article

BH3 interacting domain death agonist

PDB rendering based on 2bid.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols BID; FP497
External IDs OMIM601997 MGI108093 HomoloGene923 ChEMBL: 1250414 GeneCards: BID Gene
RNA expression pattern
PBB GE BID 204493 at tn.png
PBB GE BID 211725 s at tn.png
More reference expression data
Species Human Mouse
Entrez 637 12122
Ensembl ENSG00000015475 ENSMUSG00000004446
UniProt P55957 P70444
RefSeq (mRNA) NM_001196 NM_007544
RefSeq (protein) NP_001187 NP_031570
Location (UCSC) Chr 22:
18.22 – 18.26 Mb
Chr 6:
120.89 – 120.92 Mb
PubMed search [1] [2]
PDB 2bid EBI.jpg
human pro-apoptotic protein bid
Symbol BID
Pfam PF06393
InterPro IPR010479
SCOP 1ddb

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family.[1] Bcl-2 family members share one or more of the four characteristic domains 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.


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 protein, 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)[2] 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.[3] 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:


Caspase-8 (as surface) cleavage of Bid (as ribbon) (visualization by Kosi Gramatikoff)

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.[12] Activation of caspase-8, and subsequent BID cleavage participate in cytochrome-c mediated apoptosis.[13] 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.[14] 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.[15][16]

See also[edit]


  1. ^ Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ (1996). "BID: a novel BH3 domain-only death agonist". Genes Dev. 10 (22): 2859–69. doi:10.1101/gad.10.22.2859. PMID 8918887. 
  2. ^ Weinberg, Robert A. (2007). The biology of cancer. New York: Taylor & Francis. p. 341. ISBN 0-8153-4076-1. 
  3. ^ Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS (2002). "BID regulation by p53 contributes to chemosensitivity". Nat. Cell Biol. 4 (11): 842–9. doi:10.1038/ncb866. PMID 12402042. 
  4. ^ Liu Y, Bertram CC, Shi Q, Zinkel SS (2011). "Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress". Cell Death Differ. 18 (5): 841–52. doi:10.1038/cdd.2010.151. PMC 3074003. PMID 21113148. 
  5. ^ a b Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (2005). "Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function". Mol. Cell 17 (3): 393–403. doi:10.1016/j.molcel.2004.12.030. PMID 15694340. 
  6. ^ Real PJ, Cao Y, Wang R, Nikolovska-Coleska Z, Sanz-Ortiz J, Wang S, Fernandez-Luna JL (2004). "Breast cancer cells can evade apoptosis-mediated selective killing by a novel small molecule inhibitor of Bcl-2". Cancer Res. 64 (21): 7947–53. doi:10.1158/0008-5472.CAN-04-0945. PMID 15520201. 
  7. ^ a b Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES (2002). "Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria". J. Biol. Chem. 277 (16): 13430–7. doi:10.1074/jbc.M108029200. PMID 11832478. 
  8. ^ Paroni G, Henderson C, Schneider C, Brancolini C (2001). "Caspase-2-induced apoptosis is dependent on caspase-9, but its processing during UV- or tumor necrosis factor-dependent cell death requires caspase-3". J. Biol. Chem. 276 (24): 21907–15. doi:10.1074/jbc.M011565200. PMID 11399776. 
  9. ^ Gajate C, Mollinedo F (2005). "Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy". J. Biol. Chem. 280 (12): 11641–7. doi:10.1074/jbc.M411781200. PMID 15659383. 
  10. ^ Weng C, Li Y, Xu D, Shi Y, Tang H (2005). "Specific cleavage of Mcl-1 by caspase-3 in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in Jurkat leukemia T cells". J. Biol. Chem. 280 (11): 10491–500. doi:10.1074/jbc.M412819200. PMID 15637055. 
  11. ^ Liu Y, Vaithiyalingam S, Shi Q, Chazin WJ, Zinkel SS (2011). "BID binds to replication protein A and stimulates ATR function following replicative stress". Mol. Cell. Biol. 31 (21): 4298–309. doi:10.1128/MCB.05737-11. PMC 3209332. PMID 21859891. 
  12. ^ Singh R, Pervin S, Chaudhuri G (2002). "Caspase-8-mediated BID cleavage and release of mitochondrial cytochrome c during Nomega-hydroxy-L-arginine-induced apoptosis in MDA-MB-468 cells. Antagonistic effects of L-ornithine". J. Biol. Chem. 277 (40): 37630–6. doi:10.1074/jbc.M203648200. PMID 12145284. 
  13. ^ Tang D, Lahti JM, Kidd VJ (2000). "Caspase-8 activation and bid cleavage contribute to MCF7 cellular execution in a caspase-3-dependent manner during staurosporine-mediated apoptosis". J. Biol. Chem. 275 (13): 9303–7. doi:10.1074/jbc.275.13.9303. PMID 10734071. 
  14. ^ Viswanath V, Wu Y, Boonplueang R, Chen S, Stevenson FF, Yantiri F, Yang L, Beal MF, Andersen JK (2001). "Caspase-9 activation results in downstream caspase-8 activation and bid cleavage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease". J. Neurosci. 21 (24): 9519–28. PMID 11739563. 
  15. ^ Gu Q, Wang JD, Xia HH, Lin MC, He H, Zou B, Tu SP, Yang Y, Liu XG, Lam SK, Wong WM, Chan AO, Yuen MF, Kung HF, Wong BC (2005). "Activation of the caspase-8/Bid and Bax pathways in aspirin-induced apoptosis in gastric cancer". Carcinogenesis 26 (3): 541–6. doi:10.1093/carcin/bgh345. PMID 15579484. 
  16. ^ Anto RJ, Mukhopadhyay A, Denning K, Aggarwal BB (2002). "Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl". Carcinogenesis 23 (1): 143–50. doi:10.1093/carcin/23.1.143. PMID 11756235. 

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

BH3 interacting domain (BID) Provide feedback

BID is a member of the BCL-2 superfamily of proteins are key regulators of programmed cell death, hence this family is related to PF00452 . BID is a pro-apoptotic member of the Bcl-2 superfamily and as such posses the ability to target intracellular membranes and contains the BH3 death domain. The activity of BID is regulated by a Caspase 8-mediated cleavage event, exposing the BH3 domain and significantly changing the surface charge and hydrophobicity, which causes a change of cellular localisation [1].

Literature references

  1. McDonnell JM, Fushman D, Milliman CL, Korsmeyer SJ, Cowburn D; , Cell 1999;96:625-634.: Solution structure of the proapoptotic molecule BID: a structural basis for apoptotic agonists and antagonists. PUBMED:10089878 EPMC:10089878

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR010479

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.

BID is a member of the Bcl-2 superfamily of proteins that are key regulators of programmed cell death, hence this family is related to the Apoptosis regulator Bcl-2 protein BH domain. BID is a pro-apoptotic member of the Bcl-2 superfamily and as such posses the ability to target intracellular membranes and contains the BH3 death domain. The activity of BID is regulated by a Caspase 8-mediated cleavage event, exposing the BH3 domain and significantly changing the surface charge and hydrophobicity, which causes a change of cellular localisation [PUBMED:10089878].

Gene Ontology

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Domain organisation

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Seed source: Pfam-B_16321 (release 9.0)
Previous IDs: none
Type: Domain
Author: Finn RD
Number in seed: 7
Number in full: 65
Average length of the domain: 163.70 aa
Average identity of full alignment: 51 %
Average coverage of the sequence by the domain: 94.68 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 27.2 48.5
Noise cut-off 24.3 19.8
Model length: 196
Family (HMM) version: 6
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Species distribution

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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 BID domain has been found. There are 5 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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