Summary: EGF-like domain
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EGF-like domain Edit Wikipedia article
Structure of the epidermal growth factor-like domain of heregulin-alpha.
crystal structure of the extracellular segment of integrin alphavbeta3
The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of mostly animal proteins. Most occurrences of the EGF-like domain are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted. An exception to this is the prostaglandin-endoperoxide synthase. The EGF-like domain includes 6 cysteine residues which in the epidermal growth factor have been shown to form 3 disulfide bonds. The structures of 4-disulfide EGF-domains have been solved from the laminin and integrin proteins. The main structure of EGF-like domains is a two-stranded β-sheet followed by a loop to a short C-terminal, two-stranded β-sheet. These two β-sheets are usually denoted as the major (N-terminal) and minor (C-terminal) sheets. EGF-like domains frequently occur in numerous tandem copies in proteins: these repeats typically fold together to form a single, linear solenoid domain block as a functional unit.
Despite the similarities of EGF-like domains, distinct domain subtypes have been identified. The two main proposed types of EGF-like domains are the human EGF-like (hEGF) domain and the complement C1r-like (cEGF) domain, which was first identified in the human complement protease C1r. C1r is a highly specific serine protease initiating the classical pathway of complement activation during immune response. Both the hEGF- and cEGF-like domains contain three disulfides and derive from a common ancestor that carried four disulfides of which one was lost during evolution. Furthermore, cEGF-like domains can be divided in two subtypes (1 and 2) whereas all hEGF-like domains belong to one subtype.
The differentiation of cEGF-like and hEGF-like domains and their subtypes is based on structural features and the connectivity of their disulfide bonds. cEGF- and hEGF-like domains have a distinct shape and orientation of the minor sheet and one C-terminal half-cystine has a different position. The lost cysteines of the common ancestor differ between cEGF- and hEGF-like domains and hence these types differ in their disulfide linkages. The differentiation of cEGF into subtype 1 and 2, which probably occurred after its split from hEGF, is based on different residue numbers between the distinct half-cystines. An N-terminal located calcium binding motif can be found in hEGF- as well as in cEGF-like domains and is therefore not suitable to tell them apart.
hEGF- and cEGF-like domains also contain post-translational modifications, which are often unusual and differ between hEGF- and cEGF-like domains. These post-translational modifications include O-glycosylations, mostly O-fucose modifications, and β-hydroxylation of aspartate and asparagine residues. O-fucose modifications have only been detected in hEGF-like domains and they are important for the proper folding of the hEGF-like domain. β-Hydroxylation appears in hEGF- and cEGF-like domains, the former is hydroxylated on an aspartic acid while the latter is hydroxylated on an asparagine residue. The biological role of this post-translational modification is unclear, but mice with a knockout of the aspartyl-β-hydroxylation enzyme show developmental defects.
Proteins containing EGF-like domains are widespread and can be exclusively hEGF- or cEGF-like, or contain a mix of both. In many mitogenic and developmental proteins such as Notch and Delta the EGF-like domains are only of the hEGF type. Other proteins contain only cEGF such as thrombomodulin and the LDL-receptor. In mixed EGF-proteins the hEGF- and cEGF-like domains are grouped together with the hEGFs always being N-terminal of the cEGFs. Such proteins are involved in blood coagulation or are components of the extracellular matrix like fibrillin and LTBP-1 (Latent-transforming growth factor beta-binding protein 1). In addition to the aforementioned three disulfide hEGF- and cEGF-like types, there are proteins carrying a four-disulfide EGF-like domain like laminin and integrin.
The two main EGF-like domain subtypes hEGF and cEGF are not just distinct in their structure and conformation but also have different functions. This hypothesis is substantiated by research on LTBP-1. LTBP-1 anchors the transforming growth factor β (TGF-β) to the extracellular matrix. hEGF-like domains play a role in targeting the LTBP-1/TGF-β assembly to the extracellular matrix. Once attached to the extracellular matrix, TGF-β dissociates from hEGF subunits to allow its subsequent activation. cEGF-like domains seem to play an unspecific role in this activation by promoting the cleavage of LTBP-1 from TGF-β by various proteases.
In conclusion, although distinct EGF-like domains are grouped, subtypes can be clearly separated by their sequence, conformation and, most importantly, their function.
Role in the immune system and apoptosis
Selectins, a group of proteins that are involved in leukocyte rolling towards a source of inflammation, contain an EGF-like domain along with a lectin domain and short consensus repeats (SCRs). The functions of the EGF-like domain vary between different selectin types. Kansas and co-workers were able to show that the EGF-like domain is not required for maximal cellular adhesion in L-selectin (expressed on lymphocytes). However, it is involved in both ligand recognition and adhesion in P-selectin (expressed on platelets) and may also be involved in protein-protein interactions. It has been suggested that the interactions between lectin domains and carbohydrate ligands might be calcium-dependent.
Immature human dendritic cells appear to require interactions with the EGF-like domains of selectins during their maturation process. Blocking of this interaction with monoclonal anti-EGF-like domain antibodies prevents dendritic cell maturation. The immature cells fail to activate T-cells and produce less interleukin 12 than wild-type dendritic cells.
Phan et al. could show that the artificial insertion of an N-glycosylation site into the EGF-like domains in P- and L-selectins increased the affinities of selectins to their ligands and led to slower rolling. Therefore, EGF-like domains seem to play a crucial role in leukocyte movements towards inflammatory stimuli.
The EGF-like domain is also part of laminins, an important group of extracellular proteins. The EGF-like domains are usually masked in intact membranes, but become exposed when the membrane is destroyed, e.g. during inflammation, thereby stimulating membrane growth and restoring damaged membrane parts.
Moreover, the EGF-like domain repeats of the stabilin-2 domain have been shown to specifically recognize and bind apoptotic cells, probably by recognizing phosphatidylserine, an apoptotic cell marker (“eat me-signal”). Park et al. further demonstrated that the domains are able to competitively impair recognition of apoptotic cells by macrophages.
In conclusion, the EGF-like domain appears to play a vital role in immune responses as well as in eliminating dead cells in the organism.
Calcium-binding EGF-like domains (cbEGF-like domains) play a seminal role in diseases such as the Marfan syndrome or the X-chromosome linked hemorrhagic disorder hemophilia B  and are among the most abundant extracellular calcium-binding domains. Importantly, cbEGF- like domains impart specific functions to a variety of proteins in the blood clotting cascade. Examples include the coagulation factors VII, IX and X, protein C and its cofactor protein S.
Calcium-binding EGF-like domains are typically composed of 45 amino acids, arranged as two antiparallel beta sheets. Several cysteine residues within this sequence form disulfide bridges.
cbEGF-like domains show no significant structural deviations from EGF-like domains; however, as the name suggests, cbEGF-like domains bind a single calcium ion. The binding affinity to calcium varies widely and often depends on adjacent domains. The consensus motif for calcium binding is Asp-Leu/Ile-Asp-Gln-Cys. Coordination of calcium strongly correlates with an unusual posttranslational modification of cbEGF-like domains: either an asparagine or aspartate is beta-hydroxylated giving rise to erythro-beta-hydroxyasparagine (Hyn) or erythro-beta-hydroxyaspartic acid (Hya), respectively. Hya can be found in the N-terminal cbEGF module (see below) of factors IX, X, and protein C. The Hyn modification appears to be more prevalent than Hya and has been shown to occur in fibrillin-1, an extracellular matrix protein. Both modifications are catalyzed by the dioxygenase Asp/Asn-beta-hydroxylase, and are unique to EGF domains in eukaryotes.
Further posttranslational modifications have been reported. Glycosylation in the form of O-linked di- or trisaccharides may occur at a serine residue between the first two cysteines of blood coagulation factors VII and IX. Factor VII exhibits an O-linked fucose at Ser60.
Multiple cbEGF domains are often connected by one or two amino acids to form larger, repetitive arrays, here referred to as 'cbEGF modules'. In the blood-clotting cascade, coagulation factors VII, IX and X and protein C contain a tandem of two cbEGF modules, whereas protein S has four. Impressively, in fibrillin-1 and fibrillin-2, 43 cbEGF modules have been found. The modularity of these proteins adds complexity to protein-protein but also module-module interaction. In factors VII, IX and X, the two cbEGF modules are preceded by an N-terminal gamma-carboxyglutamic acid (Gla) containing module (the Gla module). In vitro studies on the Gla-cbEGF tandem isolated from factor X revealed a Kd-value of 0.1 mM for calcium binding  with the free calcium blood plasma concentrations being approximately 1.2 mM. Surprisingly, in the absence of the Gla module, the cbEGF module exhibits a Kd-value of 2.2 mM for calcium. Thus, the presence of the Gla module increases calcium affinity 20-fold. Similarly, the activity of Gla and serine protease modules are modified by the cbEGF modules. In the absence of calcium, the Gla and cbEGF modules are highly mobile. As the cbEGF module associates with calcium, however, movement of the Gla module is significantly restricted because the cbEGF module now adopts a conformation that locks the neighboring Gla module in a fixed position. Therefore, calcium coordination induces conformational changes which, in turn, might modulate enzymatic activity.
Impaired coordination of calcium can result in serious disorders. Defective calcium binding to coagulation factor IX contributes to the development of hemophilia B. Individuals afflicted with this hereditary disease tend to develop hemorrhages, potentially leading to life-threatening conditions. The cause of hemophilia B is decreased activity or deficiency of blood coagulation factor IX. Point mutations resulting in decreased affinity of factor IX to calcium are thought to be implicated in this bleeding disorder. On a molecular basis, it appears that hemophilia B can be the result of an impaired ability to localize the Gla module efficiently, as it usually occurs after calcium coordination by the cbEGF module in fully functional factor IX. This defect is thought to impair the biological function of factor IX. A similar problem occurs in patients suffering from hemophilia B and carrying a mutation (Glu78Lys) in factor IX that prevents interaction of the two cbEGF modules with one another. Conversely, in healthy individuals, Glu78 in the first cbEGF-module contacts Arg94 in the second cbEGF module and thereby aligns both modules. Thus, domain-domain interactions (partially facilitated by calcium coordination) are crucial for the catalytic activity of proteins involved in the blood-clotting cascade.
Proteins containing this domain
Below is a list of human proteins containing the EGF-like domain:
- AGC1; AGRIN; AREG; ATRN; ATRNL1;
- BCAN; BMP1; BTC;
- C1S; CASPR4; CD248; CD93; CELSR1; CELSR2; CELSR3; CLEC14A; CNTNAP1; CNTNAP2; CNTNAP3; CNTNAP4; CNTNAP5; COMP; COX-2; CRB1; CRB2; CSPG3; CUBN;
- DLK1; DLL1; DLL3; DLL4; DNER;
- EDIL3; EGF; EGFL11; EGFL8; EGFL9; EGFLAM; EPGN; EREG;
- F7; F9; F10; F12; FAT; FAT2; FAT4; FBN1; FBN2; FBN3;
- HABP2; HBEGF; HEG1; HGFAC; HMCN1; HSPG2;
- JAG1; JAG2;
- LDLR; LRP1; LRP10; LRP1B; LRP2; LRP4; LRP5; LRP6; LRP8; LTBP1; LTBP2; LTBP3; LTBP4;
- MATN1; MATN2; MATN3; MATN4; MEGF12; MEGF6; MEP1A; MEP1B; MFGE8; MMRN1; MMRN1; MUC4;
- NAGPA; NID1; NID2; NOTCH1; NOTCH2; NOTCH2NL; NOTCH3; NOTCH4; NRG1; NRG2; NRG3; NRG4; NRXN1; NRXN2; NRXN3; NTNG2;
- ODZ1; ODZ2; OIT3;
- PLAT; PP187; PROC; PROS1; PROZ; PTGS1; PTGS2;
- SCUBE1; SCUBE2; SCUBE3; SEL-OB; SELE; SELL; SELP; SLIT1; SLIT2; SLIT3; SNED1; STAB1; STAB2; SVEP1;
- TECTA; TGFA; THBD; THBS1; THBS2; THBS4; TIE1; TLL1; TLL2; TMEFF1; TMEFF2; TNC; TNXB;
- VASN; VCAN; VLDLR; VWA2;
- Nagata K, Kohda D, Hatanaka H, et al. (August 1994). "Solution structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erbB-4". EMBO J. 13 (15): 3517–23. PMC . PMID 8062828.
- Downing AK, Knott V, Werner JM, Cardy CM, Campbell ID, Handford PA (May 1996). "Solution structure of a pair of calcium-binding epidermal growth factor-like domains: implications for the Marfan syndrome and other genetic disorders". Cell. 85 (4): 597–605. doi:10.1016/S0092-8674(00)81259-3. PMID 8653794.
- Bork P, Downing AK, Kieffer B, Campbell ID (May 1996). "Structure and distribution of modules in extracellular proteins". Q. Rev. Biophys. 29 (2): 119–67. doi:10.1017/S0033583500005783. PMID 8870072.
- Wouters MA, Rigoutsos I, Chu CK, Feng LL, Sparrow DB, Dunwoodie SL (2005). "Evolution of distinct EGF domains with specific functions". Protein Science. 14 (4): 1091–103. doi:10.1110/ps.041207005. PMC . PMID 15772310.
- Bersch B, Hernandez JF, Marion D, Arlaud GJ (1998). "Solution Structure of the Epidermal Growth Factor (EGF)-like Module of Human Complement Protease C1r, an Atypical Member of the EGF Family". Biochemistry. 37 (5): 1204–14. doi:10.1021/bi971851v. PMID 9477945.
- Circolo A, Garnier G, Volanakis JE (2003). "A novel murine complement-related gene encoding a C1r-like serum protein". Molecular Immunology. 39 (14): 899–906. doi:10.1016/S0161-5890(02)00283-3. PMID 12686506.
- Stenflo J, Ohlin AK, Owen WG, Schneider WJ (1988). "beta-Hydroxyaspartic acid or beta-hydroxyasparagine in bovine low density lipoprotein receptor and in bovine thrombomodulin". Journal of Biological Chemistry. 263 (1): 21–24. PMID 2826439.
- Kansas GS, Saunders KB, Ley K, et al. (1994). "A role for the epidermal growth factor-like domain of P-selectin in ligand recognition and cell adhesion". J Cell Biol. 124 (4): 609–18. doi:10.1083/jcb.124.4.609. PMC . PMID 7508943.
- Phan UT, Waldron TT, Springer TA (2006). "Remodeling of the lectin-EGF-like domain interface in P- and L-selectin increases adhesiveness and shear resistance under hydrodynamic force". Nat Immunol. 7 (8): 883–9. doi:10.1038/ni1366. PMC . PMID 16845394.
- Zhou T, Zhang Y, Sun G, et al. (2006). "Anti-P-selectin lectin-EGF domain monoclonal antibody inhibits the maturation of human immature dendritic cells". Exp Mol Pathol. 80 (2): 171–6. doi:10.1016/j.yexmp.2005.10.004. PMID 16413535.
- Löffler, G; Petrides, PE; Heinrich, PC (1997). Biochemie und Pathobiochemie (5th ed.). Berlin, Heidelberg: Springer-Verlag. p. 747. ISBN 3-540-59006-4.
- Park SY, Kim SY, Jung MY, et al. (2008). "Epidermal growth factor-like domain repeat of tabilin-2 recognizes phosphatidylserine during cell corpse clearance". Mol Cell Biol. 28 (17): 5288–98. doi:10.1128/MCB.01993-07. PMC . PMID 18573870.
- Handford PA, Downing AK, Rao Z, Hewett DR, Sykes BC, Kielty CM (1991). "The calcium binding properties and molecular organization of epidermal growth factor-like domains in human fibrillin-1". J. Biol. Chem. 270 (12): 6751–6. doi:10.1074/jbc.270.12.6751. PMID 7896820.
- Handford PA, Mayhew M, Baron M, Winship PR, Campbell ID, Brownlee GG (1991). "Key residues involved in calcium-binding motifs in EGF-like domains". Nature. 351 (6322): 164–7. doi:10.1038/351164a0. PMID 2030732.
- Stenflo J, Stenberg Y, Muranyi A (2000). "Calcium-binding EGF-like modules in coagulation proteinases: function of the calcium ion in module interactions". Biochimica et Biophysica Acta. 1477 (1-2): 51–63. doi:10.1016/s0167-4838(99)00262-9. PMID 10708848.
- Glanville RW, Qian RQ, McClure DW, Maslen CL, et al. (1994). "Calcium binding, hydroxylation, and glycosylation of the precursor epidermal growth factor-like domains of fibrillin-1, the Marfan gene protein". J. Biol. Chem. 269 (43): 26630–4. PMID 7929395.
- Jia S, VanDusen WJ, Diehl RE, et al. (1992). "cDNA Cloning and Expression of Bovine Aspartyl (Asparaginyl) Beta-Hydroxylase". J. Biol. Chem. 267 (20): 14322–7. PMID 1378441.
- Valcarce C, Selander-Sunnerhagen M, Tämlitz AM, Drakenberg T, Björk I, Stenflo J (1996). "Calcium Affinity of the NH2-terminal Epidermal Growth Factor-like Module of Factor X". J. Biol. Chem. 268 (35): 26673–8. PMID 8253800.
- Nishimura H, Kawabata S, Kisiel W, et al. (1989). "Identification of a disaccharide (Xyl-Glc) and a trisaccharide (Xyl2-Glc) O-glycosidically linked to a serine residue in the first epidermal growth factor-like domain of human factors VII and IX and protein Z and bovine protein Z". J. Biol. Chem. 264 (34): 20320–5. PMID 2511201.
- Bjoern S, Foster D, Thim L, et al. (1991). "Human Plasma and Recombinant Factor VII". J. Biol. Chem. 266 (17): 11051–7. PMID 1904059.
- Piha-Gossack A, Sossin W, Reinhardt DT, et al. (2012). "The evolution of extracellular fibrillins and their functional domains". PLoS ONE. 7 (3): 33560. doi:10.1371/journal.pone.0033560. PMC . PMID 22438950.
- Sunnerhagen M, Forsen S, Hoffren A, Drakenberg T, Teleman O, Stenflo J (1995). "Structure of the Ca(2+)-free Gla domain sheds light on membrane binding of blood coagulation proteins". Nature Structural & Molecular Biology. 2 (6): 504–9. doi:10.1038/nsb0695-504. PMID 7664114.
- Sunnerhagen M, Olah GA, Stenflo J, Forsen S, Drakenberg T, Trewhella J (1996). "The relative orientation of Gla and EGF domains in coagulation factor X is altered by Ca2+ binding to the first EGF domain. A combined NMR-small angle X-ray scattering study". Biochemistry. 35 (36): 11547–59. doi:10.1021/bi960633j. PMID 8794734.
- Christophe OD, Lenting PJ, Kolkman JA, Brownlee GG, Mertens K (1988). "Blood coagulation factor IX residues Glu78 and Arg94 provide a link between both epidermal growth factor-like domains that is crucial in the interaction with factor VIII light chain". J. Biol. Chem. 273 (1): 222–27. doi:10.1074/jbc.273.1.222. PMID 9417068.
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.
EGF-like domain Provide feedback
There is no clear separation between noise and signal. PF00053 is very similar, but has 8 instead of 6 conserved cysteines. Includes some cytokine receptors. The EGF domain misses the N-terminus regions of the Ca2+ binding EGF domains (this is the main reason of discrepancy between swiss-prot domain start/end and Pfam). The family is hard to model due to many similar but different sub-types of EGF domains. Pfam certainly misses a number of EGF domains.
Downing AK, Knott V, Werner JM, Cardy CM, Campbell ID, Handford PA; , Cell 1996;85:597-605.: Solution structure of a pair of calcium-binding epidermal growth factor-like domains: implications for the Marfan syndrome and other genetic disorders. PUBMED:8653794 EPMC:8653794
Internal database links
|SCOOP:||cEGF EGF_2 EGF_3 EGF_CA EGF_MSP1_1 EGF_Tenascin FXa_inhibition hEGF Plasmod_Pvs28|
|Similarity to PfamA using HHSearch:||EGF_CA EGF_2 hEGF EGF_3 FXa_inhibition|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000742
A sequence of about thirty to forty amino-acid residues long found in the sequence of epidermal growth factor (EGF) has been shown [PUBMED:2288911, PUBMED:6334307, PUBMED:6607417, PUBMED:3282918] to be present, in a more or less conserved form, in a large number of other, mostly animal proteins. EGF is a polypeptide of about 50 amino acids with three internal disulfide bridges. It first binds with high affinity to specific cell-surface receptors and then induces their dimerization, which is essential for activating the tyrosine kinase in the receptor cytoplasmic domain, initiating a signal transduction that results in DNA synthesis and cell proliferation.
A common feature of all EGF-like domains is that they are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted (exception: prostaglandin G/H synthase). The EGF-like domain includes six cysteine residues which have been shown to be involved in disulfide bonds. The structure of several EGF-like domains has been solved. The fold consists of two-stranded beta-sheet followed by a loop to a C-terminal short two-stranded sheet.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
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Members of this clan all belong to the EGF superfamily. This particular superfamily is characterised as having least 6 cysteine residues. These cysteines form disulphide bonds, in the order 1-3, 2-4, 5-6, which are essential for the stability of the EGF fold. These disulphide bonds are stacked in a ladder-like arrangement. The Laminin EGF family is distinguished by having an an additional disulphide bond. The function of the domains within this family remains unclear, but they are thought to largely perform a structural role. More often than not, these domains are arranged in tandem repeats in extracellular proteins.
The clan contains the following 21 members:cEGF CFC DSL EGF EGF_2 EGF_3 EGF_alliinase EGF_CA EGF_MSP1_1 EGF_Tenascin Fibrillin_U_N FOLN FXa_inhibition Gla hEGF I-EGF_1 Laminin_EGF Plasmod_Pvs28 Sushi Sushi_2 Tme5_EGF_like
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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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.
|Author:||Bateman A , Sonnhammer ELL|
|Number in seed:||67|
|Number in full:||59219|
|Average length of the domain:||31.80 aa|
|Average identity of full alignment:||39 %|
|Average coverage of the sequence by the domain:||8.68 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||27|
|Download:||download the raw HMM for this family|
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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:
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".
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.
The tree shows the occurrence of this domain across different species. More...
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.
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
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.
There are 16 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 EGF domain has been found. There are 375 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 sequence.
Loading structure mapping...