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EGF-like domain

Protein domain named after the epidermal growth factor protein From Wikipedia, the free encyclopedia

EGF-like domain
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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.

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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]

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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).[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]

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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

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

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See also

References

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