AiPD: Autoinhibited Protein Database

P13387

Gene name	EGFR
Protein name	Epidermal growth factor receptor
Names	CER , EC 2.7.10.1
Species	Gallus gallus (Chicken)
KEGG Pathway	gga:396494
EC number	2.7.10.1: Protein-tyrosine kinases
Protein Class

Descriptions

Epidermal growth factor receptor plays critical roles in regulating cell proliferation, differentiation, and migration. The extracellular region of the EGF receptor contains four subdomains (domains I, II, III, and IV). Self-association of EGFR is autoinhibited by intramolecular interaction between domain II and IV, which sequesters the dimerization arm within domain II. Glycosylation of an Asn residue in domain IV induces autoinhibition while its mutation disrupts autoinhibition. Glycosylations of Asn residues within domain II reduce autoinhibition.

Autoinhibitory domains (AIDs)

489-628 (Domain IV) SS

Target domain	173-316 (Domain II)
Relief mechanism	Partner binding, PTM
Assay

AID

489-628 (Domain IV)

Target domain

173-316 (Domain II)

Relief mechanism

Partner binding (EGF binding to domain I), PTM (Deglycosylation of Asn residue within subdomain IV or glycosylation of Asn residues within domain II)

Assay

Accessory elements

No accessory elements

References

Zhang X et al. (2006) "An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor", Cell, 125, 1137-49

Ferguson KM et al. (2003) "EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization", Molecular cell, 11, 507-17

Whitson KB et al. (2005) "Functional effects of glycosylation at Asn-579 of the epidermal growth factor receptor", Biochemistry, 44, 14920-31

Contessa JN et al. (2008) "Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells", Cancer research, 68, 3803-9

Huang X et al. (2009) "Structural insights into the inhibited states of the Mer receptor tyrosine kinase", Journal of structural biology, 165, 88-96

Kovacs E et al. (2015) "Analysis of the Role of the C-Terminal Tail in the Regulation of the Epidermal Growth Factor Receptor", Molecular and cellular biology, 35, 3083-102

Autoinhibited structure

Activated structure

1 structures for P13387

Entry ID	Method	Resolution	Chain	Position	Source
AF-P13387-F1	Predicted				AlphaFoldDB

No variants for P13387

Variant ID(s)	Position	Change	Description	Diseaes Association	Provenance
No variants for P13387

No associated diseases with P13387

10 regional properties for P13387

Type	Name	Position	InterPro Accession
domain	Receptor L-domain	63 - 174	IPR000494-1
domain	Receptor L-domain	368 - 487	IPR000494-2
domain	Furin-like cysteine-rich domain	193 - 345	IPR006211
repeat	Furin-like repeat	191 - 232	IPR006212-1
repeat	Furin-like repeat	235 - 281	IPR006212-2
repeat	Furin-like repeat	503 - 554	IPR006212-3
repeat	Furin-like repeat	559 - 611	IPR006212-4
repeat	Furin-like repeat	624 - 661	IPR006212-5
domain	Growth factor receptor domain 4	512 - 647	IPR032778
domain	Epidermal growth factor receptor-like, transmembrane-juxtamembrane segment	655 - 690	IPR049328

Functions

		Description
EC Number	2.7.10.1	Protein-tyrosine kinases
Subcellular Localization	Cell membrane ; Single-pass type I membrane protein Endoplasmic reticulum membrane ; Single-pass type I membrane protein Golgi apparatus membrane ; Single-pass type I membrane protein Nucleus membrane ; Single-pass type I membrane protein Endosome Endosome membrane Nucleus	In response to EGF, translocated from the cell membrane to the nucleus via Golgi and ER Endocytosed upon activation by ligand (By similarity)
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category	No pathway information available

6 GO annotations of cellular component

Name	Definition
endoplasmic reticulum membrane	The lipid bilayer surrounding the endoplasmic reticulum.
endosome membrane	The lipid bilayer surrounding an endosome.
Golgi membrane	The lipid bilayer surrounding any of the compartments of the Golgi apparatus.
nuclear membrane	Either of the lipid bilayers that surround the nucleus and form the nuclear envelope; excludes the intermembrane space.
nucleus	A membrane-bounded organelle of eukaryotic cells in which chromosomes are housed and replicated. In most cells, the nucleus contains all of the cell's chromosomes except the organellar chromosomes, and is the site of RNA synthesis and processing. In some species, or in specialized cell types, RNA metabolism or DNA replication may be absent.
plasma membrane	The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.

3 GO annotations of molecular function

Name	Definition
ATP binding	Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator.
protein tyrosine kinase activity	Catalysis of the reaction
transmembrane receptor protein tyrosine kinase activity	Combining with a signal and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity by catalysis of the reaction

4 GO annotations of biological process

Name	Definition
cellular response to epidermal growth factor stimulus	Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an epidermal growth factor stimulus.
epidermal growth factor receptor signaling pathway	The series of molecular signals initiated by binding of a ligand to the tyrosine kinase receptor EGFR (ERBB1) on the surface of a cell. The pathway ends with regulation of a downstream cellular process, e.g. transcription.
learning or memory	The acquisition and processing of information and/or the storage and retrieval of this information over time.
phosphorylation	The process of introducing a phosphate group into a molecule, usually with the formation of a phosphoric ester, a phosphoric anhydride or a phosphoric amide.

13 homologous proteins in AiPD

UniProt AC	Gene Name	Protein Name	Species	Evidence Code
P21860	ERBB3	Receptor tyrosine-protein kinase erbB-3	Homo sapiens (Human)	SS
P04626	ERBB2	Receptor tyrosine-protein kinase erbB-2	Homo sapiens (Human)	SS
P00533	EGFR	Epidermal growth factor receptor	Homo sapiens (Human)	EV
Q15303	ERBB4	Receptor tyrosine-protein kinase erbB-4	Homo sapiens (Human)	SS
Q01279	Egfr	Epidermal growth factor receptor	Mus musculus (Mouse)	SS
P70424	Erbb2	Receptor tyrosine-protein kinase erbB-2	Mus musculus (Mouse)	SS
Q61526	Erbb3	Receptor tyrosine-protein kinase erbB-3	Mus musculus (Mouse)	SS
Q61527	Erbb4	Receptor tyrosine-protein kinase erbB-4	Mus musculus (Mouse)	SS
Q62799	Erbb3	Receptor tyrosine-protein kinase erbB-3	Rattus norvegicus (Rat)	SS
Q62956	Erbb4	Receptor tyrosine-protein kinase erbB-4	Rattus norvegicus (Rat)	SS
P06494	Erbb2	Receptor tyrosine-protein kinase erbB-2	Rattus norvegicus (Rat)	SS
P55245	EGFR	Epidermal growth factor receptor	Macaca mulatta (Rhesus macaque)	SS
O16262	nipi-4	Protein nipi-4	Caenorhabditis elegans	PR

10	20	30	40	50	60
MGVRSPLSAS	GPRGAAVLVL	LLLGVALCSA	VEEKKVCQGT	NNKLTQLGHV	EDHFTSLQRM
70	80	90	100	110	120
YNNCEVVLSN	LEITYVEHNR	DLTFLKTIQE	VAGYVLIALN	MVDVIPLENL	QIIRGNVLYD
130	140	150	160	170	180
NSFALAVLSN	YHMNKTQGLR	ELPMKRLSEI	LNGGVKISNN	PKLCNMDTVL	WNDIIDTSRK
190	200	210	220	230	240
PLTVLDFASN	LSSCPKCHPN	CTEDHCWGAG	EQNCQTLTKV	ICAQQCSGRC	RGKVPSDCCH
250	260	270	280	290	300
NQCAAGCTGP	RESDCLACRK	FRDDATCKDT	CPPLVLYNPT	TYQMDVNPEG	KYSFGATCVR
310	320	330	340	350	360
ECPHNYVVTD	HGSCVRSCNT	DTYEVEENGV	RKCKKCDGLC	SKVCNGIGIG	ELKGILSINA
370	380	390	400	410	420
TNIDSFKNCT	KINGDVSILP	VAFLGDAFTK	TLPLDPKKLD	VFRTVKEISG	FLLIQAWPDN
430	440	450	460	470	480
ATDLYAFENL	EIIRGRTKQH	GQYSLAVVNL	KIQSLGLRSL	KEISDGDIAI	MKNKNLCYAD
490	500	510	520	530	540
TMNWRSLFAT	QSQKTKIIQN	RNKNDCTADR	HVCDPLCSDV	GCWGPGPFHC	FSCRFFSRQK
550	560	570	580	590	600
ECVKQCNILQ	GEPREFERDS	KCLPCHSECL	VQNSTAYNTT	CSGPGPDHCM	KCAHFIDGPH
610	620	630	640	650	660
CVKACPAGVL	GENDTLVWKY	ADANAVCQLC	HPNCTRGCKG	PGLEGCPNGS	KTPSIAAGVV
670	680	690	700
GGLLCLVVVG	LGIGLYLRRR	HIVRKRTLRR	LLQERELVEP	LTP