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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. Most occurrences of the EGF-like domain are found in the extracellular domain of membrane protein 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 . 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 protein folding together to form a single, linear solenoid domain block as a functional unit.
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.
Either or both subtypes may be found in proteins containing EGF-like domains. In many mitogenic and developmental proteins such as Notch proteins 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.
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. (1997). 9783540590064, Springer-Verlag. ISBN 9783540590064 During apoptosis, the EGF-like domain repeats of stabilin-2 recognize and bind apoptotic cells, probably by recognizing phosphatidylserine, an apoptotic cell marker.
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. 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. Calcium binding has been found to be associated with induction of unusual posttranslational modifications of cbEGF-like domains in proteins such as fibrillin-1.
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. cbEGF modules exhibit altered calcium-binding affinity (compared to the isolated domains) and also are involved in regulation of other domains of the protein.
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, and mutations that prevent proper interactions between cbEGF domains in this protein may further complicate this disorder.
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