SMART: EGF domain annotation

EGF Epidermal growth factor-like domain.

SMART accession number:	SM00181
Description:
Interpro abstract (IPR000742):	A sequence of about thirty to forty amino-acid residues long found in the sequence of epidermal growth factor (EGF) has been shown [(PUBMED:2288911), (PUBMED:6334307), (PUBMED:1522591), (PUBMED:6607417), (PUBMED:3282918), (PUBMED:11498013)] to be present, in a more or less conserved form, in a large number of other, mostly animal proteins. The functional significance of EGF domains in what appear to be unrelated proteins is not yet clear. However, a common feature is that these repeats are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted (exception: prostaglandin G/H synthase). The EGF domain includes six cysteine residues which have been shown (in EGF) to be involved in disulphide bonds. The main structure is a two-stranded beta-sheet followed by a loop to a C-terminal short two-stranded sheet. Subdomains between the conserved cysteines vary in length.
GO function:	protein binding (GO:0005515)
Family alignment:	View or

There are 45913 EGF domains in 14726 proteins in SMART's nrdb database.

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Evolution (species in which this domain is found)
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This tree shows only several representative species. The complete taxonomic breakdown of all proteins with EGF domain is also avaliable.

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Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Takifugu rubripes
Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
- Rao Z, Handford P, Mayhew M, Knott V, Brownlee GG, Stuart D
- The structure of a Ca(2+)-binding epidermal growth factor-like domain: its role in protein-protein interactions.
- Cell. 1995; 82: 131-41
- Display abstract
- Various diverse extracellular proteins possess Ca(2+)-binding epidermal growth factor (EGF)-like domains, the function of which remains uncertain. We have determined, at high resolution (1.5 A), the crystal structure of such a domain, from human clotting factor IX, as a complex with Ca2+. The Ca2+ ligands form a classic pentagonal bipyramid with six ligands contributed by one polypeptide chain and the seventh supplied by a neighboring EGF-like domain. The crystal structure identifies the role of Ca2+ in maintaining the conformation of the N-terminal region of the domain, but more importantly demonstrates that Ca2+ can directly mediate protein-protein contacts. The observed crystal packing of the domains provides a plausible model for the association of multiple tandemly linked EGF-like domains in proteins such as fibrillin-1, Notch, and protein S. This model is consistent with the known functional data and suggests a general biological role for these domains.
- Holmes WE et al.
- Identification of heregulin, a specific activator of p185erbB2.
- Science. 1992; 256: 1205-10
- Display abstract
- The proto-oncogene designated erbB2 or HER2 encodes a 185-kilodalton transmembrane tyrosine kinase (p185erbB2), whose overexpression has been correlated with a poor prognosis in several human malignancies. A 45-kilodalton protein heregulin-alpha (HRG-alpha) that specifically induced phosphorylation of p185erbB2 was purified from the conditioned medium of a human breast tumor cell line. Several complementary DNA clones encoding related HRGs were identified, all of which are similar to proteins in the epidermal growth factor family. Scatchard analysis of the binding of recombinant HRG to a breast tumor cell line expressing p185erbB2 showed a single high affinity binding site [dissociation constant (Kd) = 105 +/- 15 picomolar]. Heregulin transcripts were identified in several normal tissues and cancer cell lines. The HRGs may represent the natural ligands for p185erbB2.
- Engel J
- EGF-like domains in extracellular matrix proteins: localized signals for growth and differentiation?
- FEBS Lett. 1989; 251: 1-7
- Display abstract
- Multidomain proteins of the extracellular matrix (ECM) play an important role in development and maintenance of cellular organization and in tissue repair. Several ECM proteins such as laminin, tenascin and thrombospondin contain domains with homology to epidermal growth factor (EGF) and exhibit growth promoting activity. The mitogenic activity of laminin is restricted to a fragment which consists of about 25 repeating domains with partial homology to EGF and comprises the rod-like inner regions of the three short arms of the four armed molecule. The mitogenic activity does not correlate with promotion of cell attachment and neurite outgrowth for which major functional sites have been found in other regions of the laminin molecule. It is suggested that EGF-like domains in laminin, in other ECM proteins and in the extracellular portions of some membrane proteins are signals for cellular growth and differentiation. Because they are integral parts of large molecules and often of supramolecular assemblies these domains are well suited to stimulate neighboring cells in a specific and vectorial way. This concept of localized growth or differentiation signals offers an attractive mechanism for the regulation of cellular development.
- Appella E, Weber IT, Blasi F
- Structure and function of epidermal growth factor-like regions in proteins.
- FEBS Lett. 1988; 231: 1-4
- Doolittle RF, Feng DF, Johnson MS
- Computer-based characterization of epidermal growth factor precursor.
- Nature. 1984; 307: 558-60
- Display abstract
- The cDNA sequence of the precursor of mouse epidermal growth factor (EGFP) has recently been reported by two groups, both of whom noted the presence of repeated similar segments, each about 40 residues long. One of these repeat units overlaps with the sequence of epidermal growth factor itself. The sequence of epidermal growth factor has been reported to be similar to that of pancreatic secretory trypsin inhibitor (PSTI) and a somewhat better match has been found with part of the sequence of bovine factor X, one of the blood coagulating factors. We report here that there is an even stronger similarity between the sequences of some of the repeat units of epidermal growth factor precursor and certain segments in factor X. This sequence similarity is also apparent in comparisons with other blood coagulation factors. On the basis of these sequence comparisons we suggest a scheme for the evolution of the epidermal growth factor precursor. We have also identified certain structural features in the precursor sequence that bear on the way in which the mature epidermal growth factor is generated.
Disease (disease genes where sequence variants are found in this domain)

Metabolism (metabolic pathways involving proteins which contain this domain)

Structure (3D structures containing this domain)

Protein	Disease
Coagulation factor IXa heavy chain (P00740) (SMART)	OMIM:306900: Hemophilia B ; Warfarin sensitivity
Thyroid peroxidase (P07202) (SMART)	OMIM:274500: Thyroid iodine peroxidase deficiency ; Goiter, congenital ; Hypothyroidism, congenital
Fibrillin-2 (P35556) (SMART)	OMIM:121050: Contractural arachnodactyly, congenital
Low-density lipoprotein receptor (P01130) (SMART)	OMIM:143890: Hypercholesterolemia, familial
Vitamin K-dependent protein S (P07225) (SMART)	OMIM:176880: Protein S deficiency
EGF-containing fibulin-like extracellular matrix protein 1 (Q12805) (SMART)	OMIM:601548: Doyne honeycomb degeneration of retina OMIM:126600: OMIM:126600: Doyne honeycomb retinal dystrophy
Delta-like protein 3 (Q9NYJ7) (SMART)	OMIM:602768: Spondylocostal dysostosis, autosomal recessive, 1 OMIM:277300:
Fibrillin-1 (P35555) (SMART)	OMIM:134797: Marfan syndrome OMIM:154700: Shprintzen-Goldberg syndrome OMIM:182212: Ectopia lentis, familial ; MASS syndrome OMIM:604308:
Activation peptide (P04070) (SMART)	OMIM:176860: Thrombophilia due to protein C deficiency ; Purpura fulminans, neonatal
Factor VII heavy chain (P08709) (SMART)	OMIM:227500: Factor VII deficiency ; {Myocardial infarction, decreased susceptibility to}

3D Structures of EGF domains in PDB

PDB code	Main view	Title
1a3p		Role of the 6-20 disulfide bridge in the structure and activity of epidermal growth factor, nmr, 20 structures
1adx		Fifth egf-like domain of thrombomodulin (tmegf5), nmr, 14 structures
1cqe		Prostaglandin h2 synthase-1 complex with flurbiprofen
1cvu		Crystal structure of arachidonic acid bound to the cyclooxygenase active site of cox-2
1cvw		Crystal structure of active site-inhibited human coagulation factor viia (des-gla)
1cx2		Cyclooxygenase-2 (prostaglandin synthase-2) complexed with a selective inhibitor, sc-558
1ddx		Crystal structure of a mixture of arachidonic acid and prostaglandin bound to the cyclooxygenase active site of cox-2: prostaglandin structure
1diy		Crystal structure of arachidonic acid bound in the cyclooxygenase active site of pghs-1
1dqb		Nmr structure of thrombomodulin egf(4-5)
1dx5		Crystal structure of the thrombin-thrombomodulin complex
1ebv		Ovine pghs-1 complexed with salicyl hydroxamic acid
1egf		Solution structure of murine epidermal growth factor determined by nmr spectroscopy and refined by energy minimization with restraints
1epg		Three-dimensional nuclear magnetic resonance structures of mouse epidermal growth factor in acidic and physiological ph solutions
1eph		Three-dimensional nuclear magnetic resonance structures of mouse epidermal growth factor in acidic and physiological ph solutions
1epi		Three-dimensional nuclear magnetic resonance structures of mouse epidermal growth factor in acidic and physiological ph solutions
1epj		Three-dimensional nuclear magnetic resonance structures of mouse epidermal growth factor in acidic and physiological ph solutions
1eqg		The 2.6 angstrom model of ovine cox-1 complexed with ibuprofen
1eqh		The 2.7 angstrom model of ovine cox-1 complexed with flurbiprofen
1esl		Insight into e-selectin(slash)ligand interaction from the crystal structure and mutagenesis of the lec(slash)egf domains
1fe2		Crystal structure of dihomo-gamma-linoleic acid bound in the cyclooxygenase channel of prostaglandin endoperoxide h synthase-1.
1fjs		Crystal structure of the inhibitor zk-807834 (ci-1031) complexed with factor xa
1fsb		Structure of the egf domain of p-selectin, nmr, 19 structures
1g1q		Crystal structure of p-selectin lectin/egf domains
1g1r		Crystal structure of p-selectin lectin/egf domains complexed with slex
1g1s		P-selectin lectin/egf domains complexed with psgl-1 peptide
1g1t		Crystal structure of e-selectin lectin/egf domains complexed with slex
1gk5		Solution structure the megf/tgfalpha44-50 chimeric growth factor
1gl4		Nidogen-1 g2/perlecan ig3 complex
1hae		Heregulin-alpha epidermal growth factor-like domain, nmr, structures
1haf		Heregulin-alpha epidermal growth factor-like domain, nmr, minimized average structure
1hcg		Structure of human des(1-45) factor xa at 2.2 angstroms resolution
1hre		Solution structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erb4
1hrf		Solution structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erb4
1ht5		The 2.75 angstrom resolution model of ovine cox-1 complexed with methyl ester flurbiprofen
1ht8		The 2.7 angstrom resolution model of ovine cox-1 complexed with alclofenac
1igx		Crystal structure of eicosapentanoic acid bound in the cyclooxygenase channel of prostaglandin endoperoxide h synthase-1.
1igz		Crystal structure of linoleic acid bound in the cyclooxygenase channel of prostaglandin endoperoxide h synthase-1.
1ijq		Crystal structure of the ldl receptor ywtd-egf domain pair
1iox		Nmr structure of human betacellulin-2
1ip0		Nmr structure of human betacellulin-2
1ivo		Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains.
1j9c		Crystal structure of tissue factor-factor viia complex
1jbu		Coagulation factor vii zymogen (egf2/protease) in complex with inhibitory exosite peptide a-183
1jl9		Crystal structure of human epidermal growth factor
1k36		Nmr structure of human epiregulin
1k37		Nmr structure of human epiregulin
1kig		Bovine factor xa
1kli		Cofactor-and substrate-assisted activation of factor viia
1klj		Crystal structure of uninhibited factor viia
1kye		Factor xa in complex with (r)-2-(3-adamantan-1-yl-ureido)-3- (3-carbamimidoyl-phenyl)-n-phenethyl-propionamide
1mox		Crystal structure of human epidermal growth factor receptor (residues 1-501) in complex with tgf-alpha
1mq5		Crystal structure of 3-chloro-n-[4-chloro-2-[[(4- chlorophenyl)amino]carbonyl]phenyl]-4-[(4-methyl-1- piperazinyl)methyl]-2-thiophenecarboxamide complexed with human factor xa
1mq6		Crystal structure of 3-chloro-n-[4-chloro-2-[[(5-chloro-2- pyridinyl)amino]carbonyl]-6-methoxyphenyl]-4-[[(4,5- dihydro-2-oxazolyl)methylamino]methyl]-2- thiophenecarboxamide complexed with human factor xa
1nql		Structure of the extracellular domain of human epidermal growth factor (egf) receptor in an inactive (low ph) complex with egf.
1p9j		Solution structure and dynamics of the egf/tgf-alpha chimera t1e
1pge		Prostaglandin h2 synthase-1 complexed with p-(2'-iodo-5'- thenoyl)hydrotropic acid (iodosuprofen)
1pgf		Prostaglandin h2 synthase-1 complexed with 1-(4- iodobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (iodoindomethacin), cis model
1pgg		Prostaglandin h2 synthase-1 complexed with 1-(4- iodobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (iodoindomethacin), trans model
1prh		The x-ray crystal structure of the membrane protein prostaglandin h2 synthase-1
1pth		The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin h2 synthase
1pxx		Crystal structure of diclofenac bound to the cyclooxygenase active site of cox-2
1q4g		2.0 angstrom crystal structure of ovine prostaglandin h2 synthase-1, in complex with alpha-methyl-4-biphenylacetic acid
1qfk		Structure of human factor viia and its implications for the triggering of blood coagulation
1rfn		Human coagulation factor ixa in complex with p-amino benzamidine
1tpg		F1-g module pair residues 1-91 (c83s) of tissue-type plasminogen activator (t-pa) (nmr, 298k, ph2.95, representative structure)
1u67		Crystal structure of arachidonic acid bound to a mutant of prostagladin h synthase-1 that forms predominantly 11- hpete.
1v3x		Factor xa in complex with the inhibitor 1-[6-methyl-4,5,6,7- tetrahydrothiazolo(5,4-c)pyridin-2-yl] carbonyl-2- carbamoyl-4-(6-chloronaphth-2-ylsulphonyl)piperazine
1w7x		Factor7- 413 complex
1w8b		Factor7 - 413 complex
1xdt		Complex of diphtheria toxin and heparin-binding epidermal growth factor
1xfe		Solution structure of the la7-egfa pair from the ldl receptor
1ygc		Short factor viia with a small molecule inhibitor
1yo8		Structure of the c-terminal domain of human thrombospondin-2
1yuf		Type alpha transforming growth factor, nmr, 16 models without energy minimization
1yug		Type alpha transforming growth factor, nmr, 15 models after ecepp/3 energy minimization
1z1y		Crystal structure of methylated pvs25, an ookinete protein from plasmodium vivax
1z27		Crystal structure of native pvs25, an ookinete protein from plasmodium vivax.
1z3g		Crystal structure of complex between pvs25 and fab fragment of malaria transmission blocking antibody 2a8
1z6e		Crystal structure of factor xa complexed to razaxaban
1zaq		Fourth egf-like domain of thrombomodulin, nmr, 12 structures
2adx		Fifth egf-like domain of thrombomodulin (tmegf5), nmr, minimized average structure
2ayl		2.0 angstrom crystal structure of manganese protoporphyrin ix-reconstituted ovine prostaglandin h2 synthase-1 complexed with flurbiprofen
2bmg		Crystal structure of factor xa in complex with 50
2bok		Factor xa - cation
2bq6		Crystal structure of factor xa in complex with 21
2bq7		Crystal structure of factor xa in complex with 43
2bqw		Crystal structure of factor xa in complex with compound 45
2bz6		Orally available factor7a inhibitor
2d1j		Factor xa in complex with the inhibitor 2-[[4-[(5- chloroindol-2-yl)sulfonyl]piperazin-1-yl] carbonyl]thieno[3,2-b]pyridine n-oxide
2ddu		Crystal structure of the third repeat domain of reelin
2e26		Crystal structure of two repeat fragment of reelin
2ei6		Factor xa in complex with the inhibitor (-)-cis-n1-[(5- chloroindol-2-yl)carbonyl]-n2-[(5-methyl-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2- cyclohexanediamine
2ei7		Factor xa in complex with the inhibitor trans-n1-[(5- chloroindol-2-yl)carbonyl]-n2-[(5-methyl-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2- cyclohexanediamine
2ei8		Factor xa in complex with the inhibitor (1s,2r,4s)-n1-[(5- chloroindol-2-yl)carbonyl]-4-(n,n-dimethylcarbamoyl)-n2- [(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl) carbonyl]-1,2-cyclohexanediamine
2fzz		Factor xa in complex with the inhibitor 1-(3-amino-1,2- benzisoxazol-5-yl)-6-(2'-(((3r)-3-hydroxy-1-pyrrolidinyl) methyl)-4-biphenylyl)-3-(trifluoromethyl)-1,4,5,6- tetrahydro-7h-pyrazolo[3,4-c]pyridin-7-one
2g00		Factor xa in complex with the inhibitor 3-(6-(2'- ((dimethylamino)methyl)-4-biphenylyl)-7-oxo-3- (trifluoromethyl)-4,5,6,7-tetrahydro-1h-pyrazolo[3,4- c]pyridin-1-yl)benzamide
2gd4		Crystal structure of the antithrombin-s195a factor xa- pentasaccharide complex
2gy5		Tie2 ligand-binding domain crystal structure
2gy7		Angiopoietin-2/tie2 complex crystal structure
2i9a		Crystal structure of the free aminoterminal fragment of urokinase type plasminogen activator (atf)
2i9b		Crystal structure of atf-urokinase receptor complex
2jkh		Factor xa - cation inhibitor complex
2k2s		Structure of the mic1-gld/mic6-egf complex from toxoplasma gondii
2k2t		Epidermal growth factor-like domain 2 from toxoplasma gondii microneme protein 6
2oye		Indomethacin-(r)-alpha-ethyl-ethanolamide bound to cyclooxygenase-1
2oyu		Indomethacin-(s)-alpha-ethyl-ethanolamide bound to cyclooxygenase-1
2p16		Factor xa in complex with the inhibitor apixaban (bms- 562247) aka 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxo-1- piperidinyl)phenyl)-4,5,6,7-tetrahydro-1h-pyrazolo[3, 4- c]pyridine-3-carboxamide
2p3f		Crystal structure of the factor xa/nap5 complex
2p3t		Crystal structure of human factor xa complexed with 3- chloro-4-(2-methylamino-imidazol-1-ylmethyl)-thiophene-2- carboxylic acid [4-chloro-2-(5-chloro-pyridin-2- ylcarbamoyl)-6-methoxy-phenyl]-amide
2p3u		Crystal structure of human factor xa complexed with 3- chloro-n-(4-chloro-2-{[(5-chloropyridin-2-yl) amino]carbonyl}-6-methoxyphenyl)-4-[(1-methyl-1h-imidazol- 2-yl)methyl]thiophene-2-carboxamide {pfizer 320663}
2p93		Factor xa in complex with the inhibitor 5-chloro-n-(2-(4-(2- oxopyridin-1(2h)-yl)benzamido)ethyl)thiophene-2-carboxamide
2p94		Factor xa in complex with the inhibitor 3-chloro-n-((1r,2s)- 2-(4-(2-oxopyridin-1(2h)-yl)benzamido)cyclohexyl)-1h- indole-6-carboxamide
2p95		Factor xa in complex with the inhibitor 5-chloro-n-((1r,2s)- 2-(4-(2-oxopyridin-1(2h)-yl)benzamido) cyclopentyl) thiophene-2-carboxamide
2pe4		Structure of human hyaluronidase 1, a hyaluronan hydrolyzing enzyme involved in tumor growth and angiogenesis
2phb		An orally efficacious factor xa inhibitor
2pr3		Factor xa inhibitor
2puq		Crystal structure of active site inhibited coagulation factor viia in complex with soluble tissue factor
2q1j		The discovery of glycine and related amino acid-based factor xa inhibitors
2ra0		X-ray structure of fxa in complex with 7-fluoroindazole
2rhp		The thrombospondin-1 polymorphism asn700ser associated with cornoary artery disease causes local and long-ranging changes in protein structure
2rnl		Solution structure of the egf-like domain from human amphiregulin
2tgf		The solution structure of human transforming growth factor alpha
2vvc		Aminopyrrolidine factor xa inhibitor
2vvu		Aminopyrrolidine factor xa inhibitor
2vvv		Aminopyrrolidine-related triazole factor xa inhibitor
2vwl		Aminopyrrolidine factor xa inhibitor
2vwm		Aminopyrrolidine factor xa inhibitor
2vwn		Aminopyrrolidine factor xa inhibitor
2vwo		Aminopyrrolidine factor xa inhibitor
2w26		Factor xa in complex with bay59-7939
2w3i		Crystal structure of fxa in complex with 4,4-disubstituted pyrrolidine-1,2-dicarboxamide inhibitor 2
2w3k		Crystal structure of fxa in complex with 4,4-disubstituted pyrrolidine-1,2-dicarboxamide inhibitor 1
2wft		Crystal structure of the human hip ectodomain
2wfx		Crystal structure of the complex between human hedgehog- interacting protein hip and sonic hedgehog in the presence of calcium
2wg3		Crystal structure of the complex between human hedgehog- interacting protein hip and desert hedgehog without calcium
2wg4		Crystal structure of the complex between human hedgehog- interacting protein hip and sonic hedgehog without calcium
3bt1		Structure of urokinase receptor, urokinase and vitronectin complex
3bt2		Structure of urokinase receptor, urokinase and vitronectin complex
3c9a		High resolution crystal structure of argos bound to the egf domain of spitz
3ca7		High resolution crystal structure of the egf domain of spitz
3cen		Factor xa in complex with the inhibitor n-(2-(((5-chloro-2- pyridinyl) amino)sulfonyl)phenyl)-4-(2-oxo-1(2h)- pyridinyl)benzamide
3cfw		L-selectin lectin and egf domains
3cs7		Factor xa in complex with the inhibitor 1-(4-methoxyphenyl)- 6-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)-3- (trifluoromethyl)-5,6-dihydro-1h-pyrazolo[3,4-c]pyridin- 7(4h)-one
3e50		Crystal structure of human insulin degrading enzyme in complex with transforming growth factor-alpha
3egf		Solution structure of murine epidermal growth factor determined by nmr spectroscopy and refined by energy minimization with restraints
3f1s		Crystal structure of protein z complexed with protein z- dependent inhibitor
3f6u		Crystal structure of human activated protein c (apc) complexed with ppack
3fby		The crystal structure of the signature domain of cartilage oligomeric matrix protein.
3g5c		Structural and biochemical studies on the ectodomain of human adam22
3gis		Crystal structure of na-free thrombin in complex with thrombomodulin
3ho3		Crystal structure of hedgehog-interacting protein (hhip)
3ho4		Crystal structure of hedgehog-interacting protein (hhip)
3ho5		Crystal structure of hedgehog-interacting protein (hhip) and sonic hedgehog (shh) complex
3pgh		Cyclooxygenase-2 (prostaglandin synthase-2) complexed with a non-selective inhibitor, flurbiprofen
3tgf		The solution structure of human transforming growth factor alpha
4cox		Cyclooxygenase-2 (prostaglandin synthase-2) complexed with a non-selective inhibitor, indomethacin
4tgf		Solution structures of human transforming growth factor alpha derived from 1*h nmr data
5cox		Uninhibited mouse cyclooxygenase-2 (prostaglandin synthase- 2)
6cox		Cyclooxygenase-2 (prostaglandin synthase-2) complexed with a selective inhibitor, sc-558 in i222 space group

Links (links to other resources describing this domain)
BLOCKS EGF_1
PFAM EGF
INTERPRO IPR000742
PROSITE EGF_1

BLOCKS	EGF_1
PFAM	EGF
INTERPRO	IPR000742
PROSITE	EGF_1