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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-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. ==Subtypes== 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. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「EGF-like domain」の詳細全文を読む スポンサード リンク
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