Summary: Pro-apoptotic Bcl-2 protein, BAD

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Wikipedia: Bcl-2-associated death promoter
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Bcl-2-associated death promoter Edit Wikipedia article

BCL2-associated agonist of cell death

Available structures

PDB

Ortholog search: PDBe, RCSB

List of PDB id codes
1G5J

Identifiers

Symbols

BAD; BBC2; BCL2L8

External IDs

OMIM: 603167 MGI: 1096330 HomoloGene: 3189 ChEMBL: 3817 GeneCards: BAD Gene

Gene Ontology
Molecular function	â¢ protein binding â¢ phospholipid binding â¢ lipid binding â¢ cysteine-type endopeptidase activator activity involved in apoptotic process â¢ protein kinase binding â¢ protein phosphatase binding â¢ protein heterodimerization activity
Cellular component	â¢ mitochondrion â¢ mitochondrial outer membrane â¢ cytosol
Biological process	â¢ glucose catabolic process â¢ apoptotic process â¢ induction of apoptosis â¢ activation of cysteine-type endopeptidase activity involved in apoptotic process â¢ epidermal growth factor receptor signaling pathway â¢ fibroblast growth factor receptor signaling pathway â¢ positive regulation of autophagy â¢ positive regulation of mitochondrial membrane potential â¢ cytokine-mediated signaling pathway â¢ positive regulation of insulin secretion â¢ positive regulation of glucokinase activity â¢ positive regulation of insulin secretion involved in cellular response to glucose stimulus â¢ glucose homeostasis â¢ positive regulation of apoptotic process â¢ positive regulation of cysteine-type endopeptidase activity involved in apoptotic process â¢ type B pancreatic cell proliferation â¢ positive regulation of B cell differentiation â¢ positive regulation of T cell differentiation â¢ ADP metabolic process â¢ ATP metabolic process â¢ regulation of mitochondrial membrane permeability â¢ pore complex assembly â¢ nerve growth factor receptor signaling pathway â¢ phosphatidylinositol-mediated signaling â¢ positive regulation of epithelial cell proliferation â¢ cellular process regulating host cell cycle in response to virus â¢ cellular response to mechanical stimulus â¢ cellular response to nicotine â¢ cellular response to lipid â¢ cellular response to hypoxia â¢ positive regulation of release of cytochrome c from mitochondria â¢ extrinsic apoptotic signaling pathway â¢ intrinsic apoptotic signaling pathway â¢ positive regulation of type B pancreatic cell development
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 11:
64.04 â 64.05 Mb

Chr 19:
6.94 â 6.95 Mb

PubMed search

[1]

[2]

Pro-apoptotic Bcl-2 protein, BAD

complex of bcl-xl with peptide from bad

Identifiers

Symbol

Bcl-2_BAD

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

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.

[edit] 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]

[edit] 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]

[edit] See also

Programmed cell death

[edit] References

^ 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): 1240â1247. doi:10.1038/sj.cdd.4401097. PMID 12404123.
^ Sheau Yu Hsu et al. (1997). "Interference of BAD (Bcl-xL/Bcl-2-Associated Death Promoter)-Induced Apoptosis in Mammalian Cells by 14â3-3 Isoforms and P11". Molecular Endocrinology 11 (12): 1858â1867. doi:10.1210/me.11.12.1858. PMID 9369453.
^ Helmreich, E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 238-43
^ E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 242
^ Foster, T.C. et al. (2001) J. Neurosci. 21, 4066-4073, "Calcineurin Links Ca++ Dysregulation with Brain Aging"(
^ ^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): 393â403. doi:10.1016/j.molcel.2004.12.030. ISSN 1097-2765. PMID 15694340.
^ 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): 16045â52. doi:10.1074/jbc.M413488200. ISSN 0021-9258. PMID 15705582.
^ 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): 2419â27. doi:10.1038/sj.onc.1202180. ISSN 0950-9232. PMID 9824152.
^ 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): 70â5. doi:10.1016/S0003-2697(02)00028-3. ISSN 0003-2697. PMID 12137781.
^ ^a ^b AyllÃ³n, VerÃ³nica; Cayla Xavier, GarcÃa 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): 1847â55. doi:10.1002/1521-4141(200207)32:7<1847::AID-IMMU1847>3.0.CO;2-7. ISSN 0014-2980. PMID 12115603.
^ 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): 1â6. doi:10.1038/71316. ISSN 1465-7392. PMID 10620799.
^ ^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): 285â91. doi:10.1016/0092-8674(95)90411-5. ISSN 0092-8674. PMID 7834748.
^ 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): 2528â34. doi:10.1110/ps.9.12.2528. ISSN 0961-8368. PMC 2144516. PMID 11206074.
^ 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): 4507â18. doi:10.1038/sj.onc.1204584. ISSN 0950-9232. PMID 11494146.
^ 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): 413â7. doi:10.1038/37144. ISSN 0028-0836. PMID 9389483.
^ 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): 5291â7. doi:10.1038/sj.onc.1203901. ISSN 0950-9232. PMID 11077446.
^ ^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): 319â30. doi:10.1023/A:1011319901057. ISSN 1360-8185. PMID 11483855.
^ 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): 525â32. doi:10.1038/sj.cdd.4400519. ISSN 1350-9047. PMID 10381646.
^ ^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): 1858â67. doi:10.1210/me.11.12.1858. ISSN 0888-8809. PMID 9369453.
^ 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): 313â9. doi:10.1016/S0167-4838(01)00202-3. ISSN 0006-3002. PMID 11410287.

[edit] Further reading

Tolstrup M, Ostergaard L, Laursen AL et al. (2004). "HIV/SIV escape from immune surveillance: focus on Nef". Curr. HIV Res. 2 (2): 141â51. doi:10.2174/1570162043484924. PMID 15078178.
Jiang P, Du W, Wu M (2007). "p53 and Bad: remote strangers become close friends". Cell Res. 17 (4): 283â5. doi:10.1038/cr.2007.19. PMID 17404594.
Yang E, Zha J, Jockel J et al. (1995). "Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death". Cell 80 (2): 285â91. doi:10.1016/0092-8674(95)90411-5. PMID 7834748.
Zha J, Harada H, Yang E et al. (1997). "Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L)". Cell 87 (4): 619â28. doi:10.1016/S0092-8674(00)81382-3. PMID 8929531.
Wang HG, Rapp UR, Reed JC (1997). "Bcl-2 targets the protein kinase Raf-1 to mitochondria". Cell 87 (4): 629â38. doi:10.1016/S0092-8674(00)81383-5. PMID 8929532.
Inohara N, Ding L, Chen S, NÃºÃ±ez G (1997). "harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L)". EMBO J. 16 (7): 1686â94. doi:10.1093/emboj/16.7.1686. PMC 1169772. PMID 9130713.
Zha J, Harada H, Osipov K et al. (1997). "BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity". J. Biol. Chem. 272 (39): 24101â4. doi:10.1074/jbc.272.39.24101. PMID 9305851.
Hsu SY, Kaipia A, Zhu L, Hsueh AJ (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. 11 (12): 1858â67. doi:10.1210/me.11.12.1858. PMID 9369453.
del Peso L, GonzÃ¡lez-GarcÃa M, Page C et al. (1997). "Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt". Science 278 (5338): 687â9. doi:10.1126/science.278.5338.687. PMID 9381178.
Ottilie S, Diaz JL, Horne W et al. (1998). "Dimerization properties of human BAD. Identification of a BH-3 domain and analysis of its binding to mutant BCL-2 and BCL-XL proteins". J. Biol. Chem. 272 (49): 30866â72. doi:10.1074/jbc.272.49.30866. PMID 9388232.
Huang DC, Adams JM, Cory S (1998). "The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4". EMBO J. 17 (4): 1029â39. doi:10.1093/emboj/17.4.1029. PMC 1170452. PMID 9463381.
Blume-Jensen P, Janknecht R, Hunter T (1998). "The kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136". Curr. Biol. 8 (13): 779â82. doi:10.1016/S0960-9822(98)70302-1. PMID 9651683.
Strobel T, Tai YT, Korsmeyer S, Cannistra SA (1998). "BAD partly reverses paclitaxel resistance in human ovarian cancer cells". Oncogene 17 (19): 2419â27. doi:10.1038/sj.onc.1202180. PMID 9824152.
Song Q, Kuang Y, Dixit VM, Vincenz C (1999). "Boo, a novel negative regulator of cell death, interacts with Apaf-1". EMBO J. 18 (1): 167â78. doi:10.1093/emboj/18.1.167. PMC 1171112. PMID 9878060.
Yasuda M, Han JW, Dionne CA et al. (1999). "BNIP3alpha: a human homolog of mitochondrial proapoptotic protein BNIP3". Cancer Res. 59 (3): 533â7. PMID 9973195.
Wang HG, Pathan N, Ethell IM et al. (1999). "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD". Science 284 (5412): 339â43. doi:10.1126/science.284.5412.339. PMID 10195903.
Holmgreen SP, Huang DC, Adams JM, Cory S (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. 6 (6): 525â32. doi:10.1038/sj.cdd.4400519. PMID 10381646.
Ostrerova N, Petrucelli L, Farrer M et al. (1999). "alpha-Synuclein shares physical and functional homology with 14-3-3 proteins". J. Neurosci. 19 (14): 5782â91. PMID 10407019.
Scheid MP, Schubert KM, Duronio V (1999). "Regulation of bad phosphorylation and association with Bcl-x(L) by the MAPK/Erk kinase". J. Biol. Chem. 274 (43): 31108â13. doi:10.1074/jbc.274.43.31108. PMID 10521512.
Bonni A, Brunet A, West AE et al. (1999). "Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms". Science 286 (5443): 1358â62. doi:10.1126/science.286.5443.1358. PMID 10558990.

[edit] External links

bcl-Associated Death Protein at the US National Library of Medicine Medical Subject Headings (MeSH)

Apoptosis signaling pathway

Fas path

Ligand	Fas ligand

Receptor	Fas receptor

Intracellular	Death-inducing signaling complex DAXX ASK1 FADD Caspase 8 BID Cytochrome c Caspase 9 Caspase 3 Pro-apoptotic: BAX BAK1/Bcl-2 homologous antagonist killer Bcl-2-associated death promoter Anti-apoptotic: Bcl-2 Bcl-xL

TNF path

Ligand	Tumor necrosis factors

Receptor	Tumor necrosis factor receptor

Intracellular	TRADD FADD Caspase 8 Caspase 3 BID TRAF2 ASK-1 MEKK1 IKK IÎºBÎ± MKK7 JNK NF-ÎºB

Other

Intracellular	IAPs XIAP NAIP Survivin c-IAP-1 c-IAP-2 Apoptosis-inducing factor

B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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

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
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
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

PANDIT:	PF10514
Pseudofam:	PF10514
SYSTERS:	Bcl-2_BAD

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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Alignments

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	Seed (4)	Full (66)	Representative proteomes				NCBI (48)	Meta (0)
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	Seed (4)	Full (66)	Representative proteomes				NCBI (48)	Meta (0)
	Seed (4)	Full (66)	RP15 (1)	RP35 (4)	RP55 (9)	RP75 (24)	NCBI (48)	Meta (0)
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	Seed (4)	Full (66)	Representative proteomes				NCBI (48)	Meta (0)
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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation

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

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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Species distribution

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Sunburst controls

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:

superkingdom
kingdom
phylum
class
order
family
genus
species

Colouring and labels

Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.

Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.

Unmapped species names

The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.

Too many species/sequences

For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

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Tree controls

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The tree shows the occurrence of this domain across different species. More...

Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

You can use the tree controls to manipulate how the interactive tree is displayed:

show/hide the summary boxes
highlight species that are represented in the seed alignment
expand/collapse the tree or expand it to a given depth
select a sub-tree or a set of species within the tree and view them graphically or as an alignment
save a plain text representation of the tree

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

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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Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Family: Bcl-2_BAD (PF10514)

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