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EGF-like domain

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EGF-like domain
Structure of the epidermal growth factor-like domain of heregulin-alpha.[1]
Identifiers
SymbolEGF
PfamPF00008
Pfam clanCL0001
ECOD389.1.1
InterProIPR000742
PROSITEPDOC00021
SCOP21apo / SCOPe / SUPFAM
CDDcd00053
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
EGF-like domain, extracellular
crystal structure of the extracellular segment of integrin alphavbeta3
Identifiers
SymbolEGF_2
PfamPF07974
Pfam clanCL0001
InterProIPR013111
CDDcd00054
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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.[2][3] 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.[4] 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.

Subtypes

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Two main subtypes of EGF-like domains have been identified:[5] The human EGF-like (hEGF) domain and the complement C1r-like (cEGF) domain.[4] The latter occurs as two subtypes, 1 and 2, whereas there is only a single hEGF-like domain subtype. 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.[4] 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. Both hEGF- and cEGF-like domains contain an N-terminal calcium binding region.[4]

Both subtypes display unusual post-translational modifications, including O-glycosylations 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.[4]

Either or both subtypes may be found in proteins containing EGF-like domains. 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 integrins.[4]

Role in the immune system and apoptosis

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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).[6][7] The functions of the EGF-like domain vary between different selectin types. For example, EGF-like domains appear essential to ligand binding by P-selectin but not L-selectin,[6] and are thus essential to the proper adhesive function of platelets. Additionally, immature human dendritic cells appear to require interactions with the EGF-like domains of selectins during their maturation process.[8]

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.[9] During apoptosis, the EGF-like domain repeats of stabilin-2 recognize and bind apoptotic cells, probably by recognizing phosphatidylserine, an apoptotic cell marker.[10]

Calcium binding

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Calcium-binding EGF-like domains (cbEGF-like domains) play a central role in diseases such as Marfan syndrome[11] or the X-chromosome linked hemorrhagic disorder hemophilia B[12] and are among the most abundant extracellular calcium-binding domains.[13] cbEGF- like domains impart specific functions to a variety of proteins in the blood clotting cascade, including coagulation factors VII, IX and X, protein C, and its cofactor protein S.[13]

Calcium-binding EGF-like domains are typically composed of 45 amino acids, arranged as two antiparallel beta sheets.[13] Several cysteine residues within this sequence form disulfide bridges. These domains show no significant structural deviations from other EGF-like domains, but can bind a single calcium ion via a consensus Asp-Leu/Ile-Asp-Gln-Cys motif. The binding affinity to calcium varies widely and often depends on adjacent domains.[13] Calcium binding has been found to be associated with induction of unusual posttranslational modifications of cbEGF-like domains in proteins such as fibrillin-1.[14]

Multiple cbEGF domains are often connected by one or two amino acids to form larger, repetitive arrays, referred to as 'cbEGF modules'. These modules may contain from 2 to 43 individual cbEGF domains.[15] cbEGF modules exhibit altered calcium-binding affinity (compared to the isolated domains) and also are involved in regulation of other domains of the protein.[16]

Mutant cbEGF-like domains with impaired calcium binding underlie some genetic disorders. For example, point mutations causing defective calcium binding to coagulation factor IX underlies some forms of hemophilia B,[13] and mutations that prevent proper interactions between cbEGF domains in this protein may further complicate this disorder.[13]

Proteins containing this domain

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Below is a list of human proteins containing the EGF-like domain:

See also

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References

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  1. ^ 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. doi:10.1002/j.1460-2075.1994.tb06658.x. PMC 395255. PMID 8062828.
  2. ^ 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. S2CID 15410014.
  3. ^ 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. S2CID 6104446.
  4. ^ a b c d e f 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 2253431. PMID 15772310.
  5. ^ 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.
  6. ^ a b 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 2119911. PMID 7508943.
  7. ^ 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 1764822. PMID 16845394.
  8. ^ 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.
  9. ^ Löffler, G; Petrides, PE; Heinrich, PC (1997). Biochemie und Pathobiochemie (5th ed.). Berlin, Heidelberg: Springer-Verlag. p. 747. ISBN 3-540-59006-4.
  10. ^ Park SY, Kim SY, Jung MY, et al. (2008). "Epidermal growth factor-like domain repeat of stabilin-2 recognizes phosphatidylserine during cell corpse clearance". Mol Cell Biol. 28 (17): 5288–98. doi:10.1128/MCB.01993-07. PMC 2519725. PMID 18573870.
  11. ^ 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.
  12. ^ 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. Bibcode:1991Natur.351..164H. doi:10.1038/351164a0. PMID 2030732. S2CID 4338236.
  13. ^ a b c d e f 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 (BBA) - Protein Structure and Molecular Enzymology. 1477 (1–2): 51–63. doi:10.1016/s0167-4838(99)00262-9. PMID 10708848.
  14. ^ 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. doi:10.1016/S0021-9258(18)47065-2. PMID 7929395.
  15. ^ Piha-Gossack A, Sossin W, Reinhardt DT, et al. (2012). "The evolution of extracellular fibrillins and their functional domains". PLOS ONE. 7 (3): 33560. Bibcode:2012PLoSO...733560P. doi:10.1371/journal.pone.0033560. PMC 3306419. PMID 22438950.
  16. ^ 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.
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