 | This articleis missing information about consensus cystine repeat, difulfide bond position (residues, inter/intra?). Please expand the article to include this information. Further details may exist on thetalk page.(March 2019) |
| EGF-like domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Structure of the epidermal growth factor-like domain of heregulin-alpha.[1] | |||||||||
| Identifiers | |||||||||
| Symbol | EGF | ||||||||
| Pfam | PF00008 | ||||||||
| Pfam clan | CL0001 | ||||||||
| ECOD | 389.1.1 | ||||||||
| InterPro | IPR000742 | ||||||||
| PROSITE | PDOC00021 | ||||||||
| SCOP2 | 1apo /SCOPe /SUPFAM | ||||||||
| CDD | cd00053 | ||||||||
| |||||||||
| EGF-like domain, extracellular | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 crystal structure of the extracellular segment of integrin alphavbeta3 | |||||||||
| Identifiers | |||||||||
| Symbol | EGF_2 | ||||||||
| Pfam | PF07974 | ||||||||
| Pfam clan | CL0001 | ||||||||
| InterPro | IPR013111 | ||||||||
| CDD | cd00054 | ||||||||
| |||||||||
TheEGF-like domain is an evolutionary conservedprotein domain, which derives its name from theepidermal growth factor where it was first described.[citation needed] It comprises about 30 to 40amino-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 ofmembrane-bound proteins or in proteins known to besecreted.[citation needed] An exception to this is theprostaglandin-endoperoxide synthase. The EGF-like domain includes 6cysteine residues which in the epidermal growth factor have been shown to form 3disulfide bonds. The crystal structures of 4-disulfide EGF-domains have beensolved from thelaminin andintegrin proteins.[citation needed] The main structure of EGF-like domains is a two-strandedβ-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 typicallyfold together to form a single, linearsolenoid domain block as a functional unit.[citation needed]
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 unusualpost-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 asNotch and Delta the EGF-like domains are only of the hEGF type. Other proteins contain only cEGF such asthrombomodulin and theLDL-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 likefibrillin 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]
Selectins, a group of proteins that are involved inleukocyte 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 byP-selectin but notL-selectin,[6] and are thus essential to the proper adhesive function of platelets. Additionally, immature humandendritic cells appear to require interactions with the EGF-like domains of selectins during their maturation process.[8]
The EGF-like domain is also part oflaminins, 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] Duringapoptosis, the EGF-like domain repeats ofstabilin-2 recognize and bind apoptotic cells, probably by recognizingphosphatidylserine, an apoptotic cell marker.[10]
Calcium-binding EGF-like domains (cbEGF-like domains) play a central role in diseases such asMarfan syndrome[11] or the X-chromosome linked hemorrhagic disorderhemophilia 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 factorsVII,IX andX,protein C, and its cofactorprotein 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 singlecalcium 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 asfibrillin-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]
Below is a list of human proteins containing the EGF-like domain: