{PDOC00913} {PS01187; EGF_CA} {BEGIN} ********************************************* * Calcium-binding EGF-like domain signature * ********************************************* A sequence of about forty amino-acid residues long found in the sequence of epidermal growth factor (EGF) has been shown [1-6] to be present in a large number of membrane-bound and extracellular, mostly animal proteins (see ). Many of these proteins require calcium for their biological function and a calcium-binding site has been found to be located at the N-terminus of some EGF-like domains [8]. Calcium-binding may be crucial for numerous protein-protein interactions. Proteins that are known or that are predicted to contain calcium-binding EGF-like domains are listed below. - Bone morphogenic protein 1 (BMP-1), a protein which induces cartilage and bone formation and which expresses metalloendopeptidase activity (1-2 copies). Homologous proteins are found in sea urchin - suBMP (1 copy) - and in Drosophila - the dorsal-ventral patterning protein tolloid (2 copies). - Caenorhabditis elegans developmental proteins lin-12 (2 out of 13 copies) and glp-1 (10 copies). - Calcium-dependent serine proteinase (CASP) which degrades the extracellular matrix proteins type I and IV collagen and fibronectin (1 copy). - Cartilage oligomeric matrix protein COMP (2 out of 4 copies). - Coagulation factors VII, IX, and X (1 out of 2 copies). - Complement C1r components (1 copy). - Complement C1s components (1 copy). - Complement-activating component of Ra-reactive factor (RARF) (1 copy). - Crumbs, an epithelial development protein from Drosophila (12 out of 29 copies). - Epidermal growth factor precursor (3 out of 9 copies). - Fibrillin 1 and fibrillin 2 (43 out of 47 copies). - Fibropellins IA (8 out of 21 copies) and III (6 out of 8 copies) from the apical lamina - a component of the extracellular matrix - of sea urchin. - Fibulin-1 (8 out of 9 copies) and fibulin-2 (9-10 out of 10-11), two extracellular matrix proteins. - Leucocyte antigen CD97 (2 out of 3 copies), cell surface glycoprotein EMR1 (5 out of 6 copies) and cell surface glycoprotein F4/80 (6 out 7 copies). - LDL receptors, which bind and transport low-density lipoproteins (1 out of 3 copies). - Neurogenic proteins Notch (21-22 out of 36), Xotch (21 out of 36), Motch (16 out of 34) and the human homolog Tan-1 (18 out of 36), Delta (2 out of 9 copies), Drosophila Serrate (5 out of 14 copies) and Slit (2 out of 7 copies). - Nidogen (also called entactin), a basement membrane protein from sea squirt (0 out of 2) and mammals (2 out of 6). - Proteoglycans versican (1 out of 2 copies) and chondroitin sulfate proteoglycan (gene PG-M) (1 out of 2 copies). - S1-5, a human extracellular protein whose ultimate activity is probably modulated by the environment (5 copies). - Thrombomodulin (fetomodulin), which together with thrombin activates protein C (2 out of 6 copies). - Thrombospondins 1 and 2 (1 out of 3 copies), 3 and 4 (2 out of 4 copies), adhesive glycoproteins that mediate cell-to-cell and cell-to-matrix interactions. - Thyroid peroxidase 1 (EC 1.11.1.8) (1 copy). - Transforming growth factor beta-1 binding protein (TGF-B1-BP) (14 out of 16 or 18 copies). - Uromodulin (Tamm-horsfall urinary glycoprotein) (THP) (2 out of 3 copies). - Vitamin K-dependent anticoagulant protein S (3 out of 4 copies). - 63 Kd sperm flagellar membrane protein from sea urchin (1 out of 3 copies). - 93 Kd protein (gene nel) from chicken (2 out of 5 copies). - Hypothetical 337.6 Kd protein T20G5.3 from Caenorhabditis elegans (1 out of 44 copies). 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. Latter is possibly hydroxylated (see ) [8]. A conserved aromatic residue as well as the second conserved negative residue are thought to be involved in stabilizing the calcium-binding site. Like 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 disulfide bond 'x': any amino acid '*': position of patterns. We have used the N-terminal part of the EGF domain as a consensus pattern. It includes the negative N-terminus and the possible hydroxylation site. -Consensus pattern: [DEQN]-x-[DEQN](2)-C-x(3,14)-C-x(3,7)-C-x-[DN]-x(4)-[FY]- x-C [The 4 C's are involved in disulfide bonds] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Expert(s) to contact by email: Downing A.K.; kristy@bioch.ox.ac.uk -Last update: May 2004 / Text revised. [ 1] Davis C.G. "The many faces of epidermal growth factor repeats." New Biol. 2:410-419(1990). PubMed=2288911 [ 2] Blomquist M.C., Hunt L.T., Barker W.C. "Vaccinia virus 19-kilodalton protein: relationship to several mammalian proteins, including two growth factors." Proc. Natl. Acad. Sci. U.S.A. 81:7363-7367(1984). PubMed=6334307 [ 3] Barker W.C., Johnson G.C., Hunt L.T., George D.G. Protein Nucl. Acid Enz. 29:54-68(1986). [ 4] Doolittle R.F., Feng D.F., Johnson M.S. "Computer-based characterization of epidermal growth factor precursor." Nature 307:558-560(1984). PubMed=6607417 [ 5] Appella E., Weber I.T., Blasi F. "Structure and function of epidermal growth factor-like regions in proteins." FEBS Lett. 231:1-4(1988). PubMed=3282918 [ 6] Campbell I.D., Bork P. Curr. Opin. Struct. Biol. 3:385-392(1993). [ 7] Rao Z., Handford P., Mayhew M., Knott V., Brownlee G.G., Stuart D. "The structure of a Ca(2+)-binding epidermal growth factor-like domain: its role in protein-protein interactions." Cell 82:131-141(1995). PubMed=7606779 [ 8] Selander-Sunnerhagen M., Ullner M., Persson E., Teleman O., Stenflo J., Drakenberg T. J. Biol. Chem. 267:19642-19649(1992). -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}