A sequence of about forty amino-acid residues long found in the sequence of
epidermal growth factor (EGF) has been shown [1,2,3,4,5,6] to be present in a large
number of membrane-bound and extracellular, mostly animal proteins (see
<PDOC00021>). 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 . 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
- 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
- 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
- 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
- Thyroid peroxidase 1 (EC 220.127.116.11) (1 copy).
- Transforming growth factor β-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  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 <PDOC00010>) . 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 .
| | | |
'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.
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