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2  structures 34  species 0  interactions 66  sequences 2  architectures

Family: Bcl-2_BAD (PF10514)

Summary: Pro-apoptotic Bcl-2 protein, BAD

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Bcl-2-associated death promoter". More...

Bcl-2-associated death promoter Edit Wikipedia article

BCL2-associated agonist of cell death
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols BAD; BBC2; BCL2L8
External IDs OMIM603167 MGI1096330 HomoloGene3189 ChEMBL: 3817 GeneCards: BAD Gene
RNA expression pattern
PBB GE BAD 1861 at tn.png
PBB GE BAD 209364 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 572 12015
Ensembl ENSG00000002330 ENSMUSG00000024959
UniProt Q92934 Q61337
RefSeq (mRNA) NM_004322 NM_007522
RefSeq (protein) NP_004313 NP_031548
Location (UCSC) Chr 11:
64.04 – 64.05 Mb
Chr 19:
6.94 – 6.95 Mb
PubMed search [1] [2]
Pro-apoptotic Bcl-2 protein, BAD
PDB 1g5j EBI.jpg
complex of bcl-xl with peptide from bad
Identifiers
Symbol Bcl-2_BAD
Pfam PF10514
InterPro IPR018868

The Bcl-2-associated death promoter (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 ,[1] 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.[2] After activation, it is able to form a heterodimer with anti-apoptotic proteins and prevent them from stopping apoptosis.

Mechanism of Action

Bax/Bak are believed to initiate apoptosis by forming a pore in the mitochondrial outer membrane that allows cytochrome c to escape into the cytoplasm and activate the pro-apoptotic caspase cascade. The anti-apoptotic Bcl-2 and Bcl-xL proteins inhibit cytochrome c release through the mitochondrial pore and also inhibit activation of the cytoplasmic caspase cascade by cytochrome c.[3]

Dephosphorylated BAD forms a heterodimer with Bcl-2 and Bcl-xL, inactivating them and thus allowing Bax/Bak-triggered apoptosis. When BAD is phosphorylated by Akt/protein kinase B (triggered by PIP3), it forms the BAD-(14-3-3)protein homodimer. This leaves Bcl-2 free to inhibit Bax-triggered apoptosis.[4] BAD phosphorylation is thus anti-apoptotic, and BAD dephosphorylation (e.g., by Ca2+-stimulated Calcineurin) is pro-apoptotic. The latter may be involved in neural diseases such as schizophrenia.[5]

Interactions

Overview of signal transduction pathways involved with apoptosis.

Bcl-2-associated death promoter has been shown to interact with BCL2-like 1,[6][7][8][9][10][11][12][13][14][15][16] BCL2L2,[6][10][17][18] Bcl-2,[6][12] BCL2-related protein A1,[6][17] YWHAQ,[6][19] YWHAZ,[20] MCL1[6][17] and S100A10.[19]

See also

References

  1. ^ Adachi M. and Imai K. (2002). "The proapoptotic BH3-only protein BAD transduces cell death signals independently of its interaction with Bcl-2". Cell death and differentiation 9 (11): 1240–1247. doi:10.1038/sj.cdd.4401097. PMID 12404123. 
  2. ^ Sheau Yu Hsu et al. (1997). "Interference of BAD (Bcl-xL/Bcl-2-Associated Death Promoter)-Induced Apoptosis in Mammalian Cells by 14–3-3 Isoforms and P11". Molecular Endocrinology 11 (12): 1858–1867. doi:10.1210/me.11.12.1858. PMID 9369453. 
  3. ^ Helmreich, E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 238-43
  4. ^ E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 242
  5. ^ Foster, T.C. et al. (2001) J. Neurosci. 21, 4066-4073, "Calcineurin Links Ca++ Dysregulation with Brain Aging"(
  6. ^ a b c d e f Chen, Lin; Willis Simon N, Wei Andrew, Smith Brian J, Fletcher Jamie I, Hinds Mark G, Colman Peter M, Day Catherine L, Adams Jerry M, Huang David C S (February 2005). "Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function". Mol. Cell (United States) 17 (3): 393–403. doi:10.1016/j.molcel.2004.12.030. ISSN 1097-2765. PMID 15694340. 
  7. ^ Jin, Zhaohui; Xin Meiguo, Deng Xingming (April 2005). "Survival function of protein kinase C{iota} as a novel nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-activated bad kinase". J. Biol. Chem. (United States) 280 (16): 16045–52. doi:10.1074/jbc.M413488200. ISSN 0021-9258. PMID 15705582. 
  8. ^ Strobel, T; Tai Y T, Korsmeyer S, Cannistra S A (November 1998). "BAD partly reverses paclitaxel resistance in human ovarian cancer cells". Oncogene (ENGLAND) 17 (19): 2419–27. doi:10.1038/sj.onc.1202180. ISSN 0950-9232. PMID 9824152. 
  9. ^ Zhang, Haichao; Nimmer Paul, Rosenberg Saul H, Ng Shi-Chung, Joseph Mary (August 2002). "Development of a high-throughput fluorescence polarization assay for Bcl-x(L)". Anal. Biochem. (United States) 307 (1): 70–5. doi:10.1016/S0003-2697(02)00028-3. ISSN 0003-2697. PMID 12137781. 
  10. ^ a b Ayllón, Verónica; Cayla Xavier, García Alphonse, Fleischer Aarne, Rebollo Angelita (July 2002). "The anti-apoptotic molecules Bcl-xL and Bcl-w target protein phosphatase 1alpha to Bad". Eur. J. Immunol. (Germany) 32 (7): 1847–55. doi:10.1002/1521-4141(200207)32:7<1847::AID-IMMU1847>3.0.CO;2-7. ISSN 0014-2980. PMID 12115603. 
  11. ^ Komatsu, K; Miyashita T, Hang H, Hopkins K M, Zheng W, Cuddeback S, Yamada M, Lieberman H B, Wang H G (January 2000). "Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis". Nat. Cell Biol. (ENGLAND) 2 (1): 1–6. doi:10.1038/71316. ISSN 1465-7392. PMID 10620799. 
  12. ^ a b Yang, E; Zha J, Jockel J, Boise L H, Thompson C B, Korsmeyer S J (January 1995). "Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death". Cell (UNITED STATES) 80 (2): 285–91. doi:10.1016/0092-8674(95)90411-5. ISSN 0092-8674. PMID 7834748. 
  13. ^ Petros, A M; Nettesheim D G, Wang Y, Olejniczak E T, Meadows R P, Mack J, Swift K, Matayoshi E D, Zhang H, Thompson C B, Fesik S W (Dec 2000). "Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies". Protein Sci. (United States) 9 (12): 2528–34. doi:10.1110/ps.9.12.2528. ISSN 0961-8368. PMC 2144516. PMID 11206074. 
  14. ^ Chattopadhyay, A; Chiang C W, Yang E (July 2001). "BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest". Oncogene (England) 20 (33): 4507–18. doi:10.1038/sj.onc.1204584. ISSN 0950-9232. PMID 11494146. 
  15. ^ Iwahashi, H; Eguchi Y, Yasuhara N, Hanafusa T, Matsuzawa Y, Tsujimoto Y (November 1997). "Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy". Nature (ENGLAND) 390 (6658): 413–7. doi:10.1038/37144. ISSN 0028-0836. PMID 9389483. 
  16. ^ Komatsu, K; Wharton W, Hang H, Wu C, Singh S, Lieberman H B, Pledger W J, Wang H G (November 2000). "PCNA interacts with hHus1/hRad9 in response to DNA damage and replication inhibition". Oncogene (ENGLAND) 19 (46): 5291–7. doi:10.1038/sj.onc.1203901. ISSN 0950-9232. PMID 11077446. 
  17. ^ a b c Bae, J; Hsu S Y, Leo C P, Zell K, Hsueh A J (October 2001). "Underphosphorylated BAD interacts with diverse antiapoptotic Bcl-2 family proteins to regulate apoptosis". Apoptosis (United States) 6 (5): 319–30. doi:10.1023/A:1011319901057. ISSN 1360-8185. PMID 11483855. 
  18. ^ Holmgreen, S P; Huang D C, Adams J M, Cory S (June 1999). "Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members". Cell Death Differ. (ENGLAND) 6 (6): 525–32. doi:10.1038/sj.cdd.4400519. ISSN 1350-9047. PMID 10381646. 
  19. ^ a b Hsu, S Y; Kaipia A, Zhu L, Hsueh A J (November 1997). "Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11". Mol. Endocrinol. (UNITED STATES) 11 (12): 1858–67. doi:10.1210/me.11.12.1858. ISSN 0888-8809. PMID 9369453. 
  20. ^ Yang, H; Masters S C, Wang H, Fu H (June 2001). "The proapoptotic protein Bad binds the amphipathic groove of 14-3-3zeta". Biochim. Biophys. Acta (Netherlands) 1547 (2): 313–9. doi:10.1016/S0167-4838(01)00202-3. ISSN 0006-3002. PMID 11410287. 

Further reading

External links


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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.

Pro-apoptotic Bcl-2 protein, BAD Provide feedback

BAD is a Bcl-2 homology domain 3 (BH3)-only pro-apoptotic member of the Bcl-2 protein family that is regulated by phosphorylation in response to survival factors [1]. Binding of BAD to mitochondria is thought to be exclusively mediated by its BH3 domain. Membrane localisation of BAD mediates membrane translocation of Bcl-XL. The C-terminal part of BAD is sufficient for membrane binding. There are two segments with differing lipid-binding preferences, LBD1 and LBD2, that are responsible for this binding: (i) LBD1 located in the proximity of the BH3 domain (amino acids 122-131) and (ii) LBD2, the putative C-terminal alpha-helix-5 [2]. Phosphorylation-regulated 14-3-3 protein binding may expose the cholesterol-preferring LBD1 and bury the LBD2, thereby mediating translocation of BAD to raft-like micro-domains [3].

Literature references

  1. Kelekar A, Chang BS, Harlan JE, Fesik SW, Thompson CB; , Mol Cell Biol. 1997;17:7040-7046.: Bad is a BH3 domain-containing protein that forms an inactivating dimer with Bcl-XL. PUBMED:9372935 EPMC:9372935

  2. She QB, Solit DB, Ye Q, O'Reilly KE, Lobo J, Rosen N; , Cancer Cell. 2005;8:287-297.: The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. PUBMED:16226704 EPMC:16226704

  3. Hekman M, Albert S, Galmiche A, Rennefahrt UE, Fueller J, Fischer A, Puehringer D, Wiese S, Rapp UR; , J Biol Chem. 2006;281:17321-17336.: Reversible membrane interaction of BAD requires two C-terminal lipid binding domains in conjunction with 14-3-3 protein binding. PUBMED:16603546 EPMC:16603546


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR018868

BAD is a Bcl-2 homology domain 3 (BH3)-only pro-apoptotic member of the Bcl-2 protein family that is regulated by phosphorylation in response to survival factors [PUBMED:9372935]. Binding of BAD to mitochondria is thought to be exclusively mediated by its BH3 domain. Membrane localisation of BAD mediates membrane translocation of Bcl-XL. The C-terminal part of BAD is sufficient for membrane binding. There are two segments with differing lipid-binding preferences, LBD1 and LBD2, that are responsible for this binding: (i) LBD1 located in the proximity of the BH3 domain (amino acids 122-131) and (ii) LBD2, the putative C-terminal alpha-helix-5 [PUBMED:16226704]. Phosphorylation-regulated 14-3-3 protein binding may expose the cholesterol-preferring LBD1 and bury the LBD2, thereby mediating translocation of BAD to raft-like micro-domains [PUBMED:16603546].

Domain organisation

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Seed source: TreeFam_TF102001
Previous IDs: none
Type: Family
Author: Buljan M, Coggill P
Number in seed: 4
Number in full: 66
Average length of the domain: 140.30 aa
Average identity of full alignment: 56 %
Average coverage of the sequence by the domain: 92.03 %

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 35.7 35.7
Noise cut-off 23.3 23.3
Model length: 167
Family (HMM) version: 4
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Structures

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_BAD domain has been found. There are 2 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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