PROSITE documentation PDOC00021

EGF-like domain signatures and profile

A sequence of about thirty to 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 more or less conserved form, in a large number of other, mostly animal proteins. EGF is a polypeptide of about 50 amino acids with three internal disulfide bridges. It first binds with high affinity to specific cell-surface receptors and then induces their dimerization, which is essential for activating the tyrosine kinase in the receptor cytoplasmic domain, initiating a signal transduction that results in DNA synthesis and cell proliferation.

A common feature of all EGF-like domains is that they are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted (exception: prostaglandin G/H synthase). The EGF-like domain includes six cysteine residues which have been shown to be involved in disulfide bonds. The structure of several EGF-like domains has been solved. The fold consists of two-stranded β-sheet followed by a loop to a C-terminal short two-stranded sheet (see <PDB:1EGF>). Subdomains between the conserved cysteines strongly vary in length as shown in the following schematic representation of the EGF-like domain:

                 +-------------------+        +-------------------------+
                 |                   |        |                         |
  x(4)-C-x(0,48)-C-x(3,12)-C-x(1,70)-C-x(1,6)-C-x(2)-G-a-x(0,21)-G-x(2)-C-x
       |                   |         ************************************
       +-------------------+

'C': conserved cysteine involved in a disulfide bond.
'G': often conserved glycine
'a': often conserved aromatic amino acid
'*': position of both patterns.
'x': any residue

Some proteins known to contain one or more copies of an EGF-like domain are listed below.

• Adipocyte differentiation inhibitor (gene PREF-1) from mouse (6 copies).
• Agrin, a basal lamina protein that causes the aggregation of acetylcholine receptors on cultured muscle fibers (4 copies).
• Amphiregulin, a growth factor (1 copy).
• βcellulin, a growth factor (1 copy).
• Blastula proteins BP10 and Span from sea urchin which are thought to be involved in pattern formation (1 copy).
• BM86, a glycoprotein antigen of cattle tick (7 copies).
• 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 (13 copies) and glp-1 (10 copies).
• Caenorhabditis elegans apx-1 protein, a patterning protein (4.5 copies).
• Calcium-dependent serine proteinase (CASP) which degrades the extracellular matrix proteins type I and IV collagen and fibronectin (1 copy).
• Cartilage matrix protein CMP (1 copy).
• Cartilage oligomeric matrix protein COMP (4 copies).
• Cell surface antigen 114/A10 (3 copies).
• Cell surface glycoprotein complex transmembrane subunit ASGP-2 from rat (2 copies).
• Coagulation associated proteins C, Z (2 copies) and S (4 copies).
• Coagulation factors VII, IX, X and XII (2 copies).
• Complement C1r components (1 copy).
• Complement C1s components (1 copy).
• Complement-activating component of Ra-reactive factor (RARF) (1 copy).
• Complement components C6, C7, C8 α and β chains, and C9 (1 copy).
• Crumbs, an epithelial development protein from Drosophila (29 copies).
• Epidermal growth factor precursor (7-9 copies).
• Exogastrula-inducing peptides A, C, D and X from sea urchin (1 copy).
• Fat protein, a Drosophila cadherin-related tumor suppressor (5 copies).
• Fetal antigen 1, a probable neuroendocrine differentiation protein, which is derived from the delta-like protein (DLK) (6 copies).
• Fibrillin 1 (47 copies) and fibrillin 2 (14 copies).
• Fibropellins IA (21 copies), IB (13 copies), IC (8 copies), II (4 copies) and III (8 copies) from the apical lamina - a component of the extracellular matrix - of sea urchin.
• Fibulin-1 and -2, two extracellular matrix proteins (9-11 copies).
• Giant-lens protein (protein Argos), which regulates cell determination and axon guidance in the Drosophila eye (1 copy).
• Growth factor-related proteins from various poxviruses (1 copy).
• Gurken protein, a Drosophila developmental protein (1 copy).
• Heparin-binding EGF-like growth factor (HB-EGF), transforming growth factor α (TGF-α), growth factors Lin-3 and Spitz (1 copy); the precursors are membrane proteins, the mature form is located extracellular.
• Hepatocyte growth factor (HGF) activator (EC 3.4.21.-) (2 copies).
• LDL and VLDL receptors, which bind and transport low-density lipoproteins and very low-density lipoproteins (3 copies).
• LDL receptor-related protein (LRP), which may act as a receptor for endocytosis of extracellular ligands (22 copies).
• Leucocyte antigen CD97 (3 copies), cell surface glycoprotein EMR1 (6 copies) and cell surface glycoprotein F4/80 (7 copies).
• Limulus clotting factor C, which is involved in hemostasis and host defense mechanisms in japanese horseshoe crab (1 copy).
• Meprin A α subunit, a mammalian membrane-bound endopeptidase (1 copy).
• Milk fat globule-EGF factor 8 (MFG-E8) from mouse (2 copies).
• Neuregulin GGF-I and GGF-II, two human glial growth factors (1 copy).
• Neurexins from mammals (3 copies).
• Neurogenic proteins Notch, Xotch and the human homolog Tan-1 (36 copies), Delta (9 copies) and the similar differentiation proteins Lag-2 from Caenorhabditis elegans (2 copies), Serrate (14 copies) and Slit (7 copies) from Drosophila.
• Nidogen (also called entactin), a basement membrane protein from chordates (2-6 copies).
• Ookinete surface proteins (24 Kd, 25 Kd, 28 Kd) from Plasmodium (4 copies).
• Pancreatic secretory granule membrane major glycoprotein GP2 (1 copy).
• Perforin, which lyses non-specifically a variety of target cells (1 copy).
• Proteoglycans aggrecan (1 copy), versican (2 copies), perlecan (at least 2 copies), brevican (1 copy) and chondroitin sulfate proteoglycan (gene PG-M) (2 copies).
• Prostaglandin G/H synthase 1 and 2 (EC 1.14.99.1) (1 copy), which is found in the endoplasmatic reticulum.
• Reelin, an extracellular matrix protein that plays a role in layering of neurons in the cerebral cortex and cerebellum of mammals (8 copies).
• S1-5, a human extracellular protein whose ultimate activity is probably modulated by the environment (5 copies).
• Schwannoma-derived growth factor (SDGF), an autocrine growth factor as well as a mitogen for different target cells (1 copy).
• Selectins. Cell adhesion proteins such as ELAM-1 (E-selectin), GMP-140 (P-selectin), or the lymph-node homing receptor (L-selectin) (1 copy).
• Serine/threonine-protein kinase homolog (gene Pro25) from Arabidopsis thaliana, which may be involved in assembly or regulation of light-harvesting chlorophyll A/B protein (2 copies).
• Sperm-egg fusion proteins PH-30 α and β from guinea pig (1 copy).
• Stromal cell derived protein-1 (SCP-1) from mouse (6 copies).
• TDGF-1, human teratocarcinoma-derived growth factor 1 (1 copy).
• Tenascin (or neuronectin), an extracellular matrix protein from mammals (14.5 copies), chicken (TEN-A) (13.5 copies) and the related proteins human tenascin-X (18 copies) and tenascin-like proteins TEN-A and TEN-M from Drosophila (8 copies).
• Thrombomodulin (fetomodulin), which together with thrombin activates protein C (6 copies).
• Thrombospondin 1, 2 (3 copies), 3 and 4 (4 copies), adhesive glycoproteins that mediate cell-to-cell and cell-to-matrix interactions.
• Thyroid peroxidase 1 and 2 (EC 2.7.10.1) from human (1 copy).
• Transforming growth factor β-1 binding protein (TGF-B1-BP) (16 or 18 copies).
• Tyrosine-protein kinase receptors Tek and Tie (EC 2.7.1.112) (3 copies).
• Urokinase-type plasminogen activator (EC 3.4.21.73) (UPA) and tissue plasminogen activator (EC 3.4.21.68) (TPA) (1 copy).
• Uromodulin (Tamm-horsfall urinary glycoprotein) (THP) (3 copies).
• Vitamin K-dependent anticoagulants protein C (2 copies) and protein S (4 copies) and the similar protein Z, a single-chain plasma glycoprotein of unknown function (2 copies).
• 63 Kd sperm flagellar membrane protein from sea urchin (3 copies).
• 93 Kd protein (gene nel) from chicken (5 copies).
• Hypothetical 337.6 Kd protein T20G5.3 from Caenorhabditis elegans (44 copies).

The region between the 5th and 6th cysteine contains two conserved glycines of which at least one is present in most EGF-like domains. We created two patterns for this domain, each including one of these C-terminal conserved glycine residues. The profile we developed covers the whole domain.