PROSITE documentation PDOC00913
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 [1,2,3,4,5,6] 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 [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 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 [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 <PDOC00010>) [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].

                             +------------------+        +---------+
                             |                  |        |         |
'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.

Expert(s) to contact by email:

Downing A.K.

Last update:

May 2004 / Text revised.


Technical section

PROSITE method (with tools and information) covered by this documentation:

EGF_CA, PS01187; Calcium-binding EGF-like domain signature  (PATTERN)


1AuthorsDavis C.G.
TitleThe many faces of epidermal growth factor repeats.
SourceNew Biol. 2:410-419(1990).
PubMed ID2288911

2AuthorsBlomquist M.C. Hunt L.T. Barker W.C.
TitleVaccinia virus 19-kilodalton protein: relationship to several mammalian proteins, including two growth factors.
SourceProc. Natl. Acad. Sci. U.S.A. 81:7363-7367(1984).
PubMed ID6334307

3AuthorsBarker W.C. Johnson G.C. Hunt L.T. George D.G.
SourceProtein Nucl. Acid Enz. 29:54-68(1986).

4AuthorsDoolittle R.F. Feng D.F. Johnson M.S.
TitleComputer-based characterization of epidermal growth factor precursor.
SourceNature 307:558-560(1984).
PubMed ID6607417

5AuthorsAppella E. Weber I.T. Blasi F.
TitleStructure and function of epidermal growth factor-like regions in proteins.
SourceFEBS Lett. 231:1-4(1988).
PubMed ID3282918

6AuthorsCampbell I.D. Bork P.
SourceCurr. Opin. Struct. Biol. 3:385-392(1993).

7AuthorsRao Z. Handford P. Mayhew M. Knott V. Brownlee G.G. Stuart D.
TitleThe structure of a Ca(2+)-binding epidermal growth factor-like domain: its role in protein-protein interactions.
SourceCell 82:131-141(1995).
PubMed ID7606779

8AuthorsSelander-Sunnerhagen M. Ullner M. Persson E. Teleman O. Stenflo J. Drakenberg T.
SourceJ. Biol. Chem. 267:19642-19649(1992).

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