A sequence of about forty amino-acid residues found in epidermal growth factor (EGF) has been shown [1, 2, 3, 4, 5] to be present in a large number of membrane-bound and extracellular, mostly animal, proteins. Many of these proteins require calcium for their biological function and a calcium-binding site has been found at the N terminus of some EGF-like domains [6]. Calcium-binding may be crucial for numerous protein-protein interactions.

For human coagulation factor IX it has been shown [7] that the calcium-ligands form a pentagonal bipyramid. The first, third and fourth conserved negatively charged or polar residues are side chain ligands. The latter is possibly hydroxylated (see aspartic acid and asparagine hydroxylation site) [8]. A conserved aromatic residue, as well as the second conserved negative residue, are thought to be involved in stabilising the calcium-binding site.

As in non-calcium binding EGF-like domains, there are six conserved cysteines and the structure of both types is very similar as calcium-binding induces only strictly local structural changes [8].

 +------------------+ +---------+ | | | | nxnnC-x(3,14)-C-x(3,7)-CxxbxxxxaxC-x(1,6)-C-x(8,13)-Cx | | +------------------+'n': negatively charged or polar residue [DEQN]'b': possibly beta-hydroxylated residue [DN]'a': aromatic amino acid'C': cysteine, involved in disulphide bond'x': any amino acid.

1. The many faces of epidermal growth factor repeats. New Biol. 2, 410-9
2. Vaccinia virus 19-kilodalton protein: relationship to several mammalian proteins, including two growth factors. Proc. Natl. Acad. Sci. U.S.A. 81, 7363-7
3. [Similar domains in different proteins: detection and significance] Tanpakushitsu Kakusan Koso , 54-68
4. Computer-based characterization of epidermal growth factor precursor. Nature 307, 558-60
5. Structure and function of epidermal growth factor-like regions in proteins. FEBS Lett. 231, 1-4
6. How an epidermal growth factor (EGF)-like domain binds calcium. High resolution NMR structure of the calcium form of the NH2-terminal EGF-like domain in coagulation factor X. J. Biol. Chem. 267, 19642-9
7. The structure of a Ca(2+)-binding epidermal growth factor-like domain: its role in protein-protein interactions. Cell 82, 131-41

A sequence of about forty amino-acid residues found in epidermal growth factor (EGF) has been
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