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Protein

Receptor tyrosine-protein kinase erbB-4

Gene

ERBB4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis.22 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation4 Publications

Enzyme regulationi

Binding of a cognate ligand leads to dimerization and activation by autophosphorylation on tyrosine residues. In vitro kinase activity is increased by Mg2+. Inhibited by PD153035, lapatinib, gefitinib (iressa, ZD1839), AG1478 and BIBX1382BS.5 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei751 – 7511ATPPROSITE-ProRule annotation
Active sitei843 – 8431Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi724 – 7329ATPPROSITE-ProRule annotation
Nucleotide bindingi797 – 7993ATPPROSITE-ProRule annotation
Nucleotide bindingi843 – 8486ATPPROSITE-ProRule annotation

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • epidermal growth factor receptor binding Source: UniProtKB
  • phosphatidylinositol-4,5-bisphosphate 3-kinase activity Source: Reactome
  • protein homodimerization activity Source: UniProtKB
  • protein tyrosine kinase activity Source: UniProtKB
  • Ras guanyl-nucleotide exchange factor activity Source: Reactome
  • receptor signaling protein tyrosine kinase activity Source: InterPro
  • transcription regulatory region DNA binding Source: UniProtKB
  • transmembrane receptor protein tyrosine kinase activity Source: UniProtKB

GO - Biological processi

  • cardiac muscle tissue regeneration Source: UniProtKB
  • cell fate commitment Source: Ensembl
  • cell migration Source: UniProtKB
  • cell proliferation Source: ProtInc
  • central nervous system morphogenesis Source: UniProtKB
  • embryonic pattern specification Source: UniProtKB
  • ERBB2 signaling pathway Source: Reactome
  • heart development Source: UniProtKB
  • lactation Source: UniProtKB
  • mammary gland alveolus development Source: UniProtKB
  • mammary gland epithelial cell differentiation Source: UniProtKB
  • MAPK cascade Source: Reactome
  • mitochondrial fragmentation involved in apoptotic process Source: UniProtKB
  • negative regulation of apoptotic process Source: UniProtKB
  • negative regulation of cell proliferation Source: UniProtKB
  • negative regulation of neuron migration Source: Ensembl
  • nervous system development Source: UniProtKB
  • neural crest cell migration Source: UniProtKB
  • olfactory bulb interneuron differentiation Source: UniProtKB
  • peptidyl-tyrosine phosphorylation Source: UniProtKB
  • phosphatidylinositol-mediated signaling Source: Reactome
  • positive regulation of cardiac muscle cell proliferation Source: UniProtKB
  • positive regulation of cell proliferation Source: UniProtKB
  • positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
  • positive regulation of phosphatidylinositol 3-kinase activity Source: UniProtKB
  • positive regulation of phosphatidylinositol 3-kinase signaling Source: Ensembl
  • positive regulation of protein localization to cell surface Source: Ensembl
  • positive regulation of protein phosphorylation Source: UniProtKB
  • positive regulation of STAT protein import into nucleus Source: UniProtKB
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of tyrosine phosphorylation of Stat5 protein Source: UniProtKB
  • protein autophosphorylation Source: UniProtKB
  • regulation of cell migration Source: UniProtKB
  • regulation of cell motility Source: Reactome
  • regulation of phosphatidylinositol 3-kinase signaling Source: Reactome
  • signal transduction Source: UniProtKB
  • transcription, DNA-templated Source: UniProtKB-KW
  • transmembrane receptor protein tyrosine kinase signaling pathway Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Activator, Developmental protein, Kinase, Receptor, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Apoptosis, Lactation, Transcription, Transcription regulation

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1. 2681.
ReactomeiR-HSA-1227986. Signaling by ERBB2.
R-HSA-1236394. Signaling by ERBB4.
R-HSA-1250196. SHC1 events in ERBB2 signaling.
R-HSA-1250342. PI3K events in ERBB4 signaling.
R-HSA-1250347. SHC1 events in ERBB4 signaling.
R-HSA-1251985. Nuclear signaling by ERBB4.
R-HSA-1253288. Downregulation of ERBB4 signaling.
R-HSA-1257604. PIP3 activates AKT signaling.
R-HSA-1963640. GRB2 events in ERBB2 signaling.
R-HSA-1963642. PI3K events in ERBB2 signaling.
R-HSA-2219530. Constitutive Signaling by Aberrant PI3K in Cancer.
R-HSA-5673001. RAF/MAP kinase cascade.
R-HSA-6785631. ERBB2 Regulates Cell Motility.
R-HSA-6811558. PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
R-HSA-8847993. ERBB2 Activates PTK6 Signaling.
SignaLinkiQ15303.
SIGNORiQ15303.

Protein family/group databases

TCDBi1.A.87.2.6. the mechanosensitive calcium channel (mca) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Receptor tyrosine-protein kinase erbB-4 (EC:2.7.10.1)
Alternative name(s):
Proto-oncogene-like protein c-ErbB-4
Tyrosine kinase-type cell surface receptor HER4
p180erbB4
Cleaved into the following chain:
ERBB4 intracellular domain
Short name:
4ICD
Short name:
E4ICD
Alternative name(s):
s80HER4
Gene namesi
Name:ERBB4
Synonyms:HER4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:3432. ERBB4.

Subcellular locationi

ERBB4 intracellular domain :

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini26 – 651626ExtracellularSequence analysisAdd
BLAST
Transmembranei652 – 67524HelicalSequence analysisAdd
BLAST
Topological domaini676 – 1308633CytoplasmicSequence analysisAdd
BLAST

GO - Cellular componenti

  • basolateral plasma membrane Source: BHF-UCL
  • cytosol Source: Reactome
  • extracellular region Source: Reactome
  • integral component of membrane Source: UniProtKB-KW
  • mitochondrial matrix Source: Reactome
  • mitochondrion Source: UniProtKB
  • nucleoplasm Source: Reactome
  • nucleus Source: UniProtKB
  • plasma membrane Source: Reactome
  • receptor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane, Mitochondrion, Nucleus

Pathology & Biotechi

Involvement in diseasei

Amyotrophic lateral sclerosis 19 (ALS19)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases.
See also OMIM:615515
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti927 – 9271R → Q in ALS19; reduces autophosphorylation upon NRG1 stimulation. 1 Publication
Corresponds to variant rs397514262 [ dbSNP | Ensembl ].
VAR_070810
Natural varianti1275 – 12751R → W in ALS19; reduces autophosphorylation upon NRG1 stimulation. 1 Publication
Corresponds to variant rs397514263 [ dbSNP | Ensembl ].
VAR_070811

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi646 – 6461Q → C: Constitutively activated kinase. 1 Publication
Mutagenesisi675 – 6751V → A: Abolishes proteolytic processing and nuclear localization. 2 Publications
Mutagenesisi681 – 6844KKKR → EIMG: Abolishes nuclear localization of the ERBB4 intracellular domain. 1 Publication
Mutagenesisi710 – 7101L → N: Strongly reduced autophosphorylation. 1 Publication
Mutagenesisi721 – 7211V → I: No effect on kinase activity. 1 Publication
Mutagenesisi751 – 7511K → R: Abolishes kinase activity. Abolishes phosphorylation, proteolytic processing and nuclear localization. 3 Publications
Mutagenesisi766 – 7661M → R: Strongly reduced autophosphorylation. 1 Publication
Mutagenesisi773 – 7731A → S: No effect on kinase activity. 1 Publication
Mutagenesisi782 – 7821R → Q: No effect on kinase activity. 1 Publication
Mutagenesisi810 – 8101E → K: No effect on kinase activity. 1 Publication
Mutagenesisi843 – 8431D → N: Loss of kinase activity. 1 Publication
Mutagenesisi854 – 8541P → Q: No effect on kinase activity. 1 Publication
Mutagenesisi861 – 8611D → Y: Loss of kinase activity. 1 Publication
Mutagenesisi864 – 8641L → R: Strongly reduced autophosphorylation. 1 Publication
Mutagenesisi872 – 8721E → K: No effect on kinase activity. 1 Publication
Mutagenesisi926 – 9261T → M: No effect on kinase activity. 1 Publication
Mutagenesisi947 – 9471I → R: Constitutively autophosphorylated. 1 Publication
Mutagenesisi992 – 9921R → A: Abolishes APC/C-mediated degradation; when associated with A-995 and A-1000. 1 Publication
Mutagenesisi995 – 9951L → A: Abolishes APC/C-mediated degradation; when associated with A-992 and A-1000. 1 Publication
Mutagenesisi1000 – 10001D → A: Abolishes APC/C-mediated degradation; when associated with A-992 and A-995. 1 Publication
Mutagenesisi1035 – 10351Y → A: No effect on interaction with WWOX. Abolishes interaction with WWOX; when associated with A-1301. 1 Publication
Mutagenesisi1056 – 10561Y → A: Abolishes interaction with NEDD4 and impairs ubiquitination. Promotes nuclear translocation of ERBB4 intracellular domain E4ICD1. 1 Publication
Mutagenesisi1056 – 10561Y → F: Abolishes interaction with WWP1; when associated with F-1301. 1 Publication
Mutagenesisi1301 – 13011Y → A: Abolishes interaction with NEDD4 and impairs ubiquitination. 3 Publications
Mutagenesisi1301 – 13011Y → A: No effect on interaction with WWOX. Abolishes interaction with WWOX; when associated with A-1035. Loss of interaction with YAP1 and stimulation of transcription. 3 Publications
Mutagenesisi1301 – 13011Y → F: Abolishes interaction with WWP1; when associated with F-1056. 3 Publications

Keywords - Diseasei

Amyotrophic lateral sclerosis, Disease mutation, Neurodegeneration

Organism-specific databases

MalaCardsiERBB4.
MIMi615515. phenotype.
Orphaneti803. Amyotrophic lateral sclerosis.
PharmGKBiPA27847.

Chemistry

ChEMBLiCHEMBL2363049.
DrugBankiDB08916. Afatinib.
GuidetoPHARMACOLOGYi1799.

Polymorphism and mutation databases

BioMutaiERBB4.
DMDMi3913590.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2525Sequence analysisAdd
BLAST
Chaini26 – 13081283Receptor tyrosine-protein kinase erbB-4PRO_0000016674Add
BLAST
Chaini676 – 1308633ERBB4 intracellular domainBy similarityPRO_0000396797Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi29 ↔ 561 Publication
Glycosylationi138 – 1381N-linked (GlcNAc...)1 Publication
Disulfide bondi156 ↔ 1861 Publication
Glycosylationi174 – 1741N-linked (GlcNAc...)1 Publication
Glycosylationi181 – 1811N-linked (GlcNAc...)Sequence analysis
Disulfide bondi189 ↔ 1971 Publication
Disulfide bondi193 ↔ 2051 Publication
Disulfide bondi213 ↔ 2211 Publication
Disulfide bondi217 ↔ 2291 Publication
Disulfide bondi230 ↔ 2381 Publication
Disulfide bondi234 ↔ 2461 Publication
Disulfide bondi249 ↔ 2581 Publication
Glycosylationi253 – 2531N-linked (GlcNAc...)1 Publication
Disulfide bondi262 ↔ 2891 Publication
Disulfide bondi293 ↔ 3041 Publication
Disulfide bondi308 ↔ 3231 Publication
Disulfide bondi326 ↔ 3301 Publication
Glycosylationi358 – 3581N-linked (GlcNAc...)1 Publication
Glycosylationi410 – 4101N-linked (GlcNAc...)1 Publication
Glycosylationi473 – 4731N-linked (GlcNAc...)1 Publication
Glycosylationi495 – 4951N-linked (GlcNAc...)1 Publication
Disulfide bondi503 ↔ 5121 Publication
Disulfide bondi507 ↔ 5201 Publication
Disulfide bondi523 ↔ 5321 Publication
Disulfide bondi536 ↔ 5521 Publication
Glycosylationi548 – 5481N-linked (GlcNAc...)Sequence analysis
Disulfide bondi555 ↔ 5691 Publication
Disulfide bondi559 ↔ 5771 Publication
Glycosylationi576 – 5761N-linked (GlcNAc...)1 Publication
Disulfide bondi580 ↔ 5891 Publication
Disulfide bondi593 ↔ 6141 Publication
Disulfide bondi617 ↔ 6251 Publication
Glycosylationi620 – 6201N-linked (GlcNAc...)Sequence analysis
Disulfide bondi621 ↔ 6331 Publication
Modified residuei875 – 8751Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1035 – 10351Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1056 – 10561Phosphotyrosine; by autocatalysis3 Publications
Modified residuei1150 – 11501Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1162 – 11621Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1188 – 11881Phosphotyrosine; by autocatalysis2 Publications
Modified residuei1202 – 12021Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1242 – 12421Phosphotyrosine; by autocatalysis2 Publications
Modified residuei1258 – 12581Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1284 – 12841Phosphotyrosine; by autocatalysis1 Publication

Post-translational modificationi

Isoform JM-A CYT-1 and isoform JM-A CYT-2 are processed by ADAM17. Proteolytic processing in response to ligand or 12-O-tetradecanoylphorbol-13-acetate stimulation results in the production of 120 kDa soluble receptor forms and intermediate membrane-anchored 80 kDa fragments (m80HER4), which are further processed by a presenilin-dependent gamma-secretase to release a cytoplasmic intracellular domain (E4ICD; E4ICD1/s80Cyt1 or E4ICD2/s80Cyt2, depending on the isoform). Membrane-anchored 80 kDa fragments of the processed isoform JM-A CYT-1 are more readily degraded by the proteasome than fragments of isoform JM-A CYT-2, suggesting a prevalence of E4ICD2 over E4ICD1. Isoform JM-B CYT-1 and isoform JM-B CYT-2 lack the ADAM17 cleavage site and are not processed by ADAM17, precluding further processing by gamma-secretase.6 Publications
Autophosphorylated on tyrosine residues in response to ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Ligands trigger phosphorylation at specific tyrosine residues, thereby creating binding sites for scaffold proteins and effectors. Constitutively phosphorylated at a basal level when overexpressed in heterologous systems; ligand binding leads to increased phosphorylation. Phosphorylation at Tyr-1035 is important for interaction with STAT1. Phosphorylation at Tyr-1056 is important for interaction with PIK3R1. Phosphorylation at Tyr-1242 is important for interaction with SHC1. Phosphorylation at Tyr-1188 may also contribute to the interaction with SHC1. Isoform JM-A CYT-2 is constitutively phosphorylated on tyrosine residues in a ligand-independent manner. E4ICD2 but not E4ICD1 is phosphorylated on tyrosine residues.7 Publications
Ubiquitinated. During mitosis, the ERBB4 intracellular domain is ubiquitinated by the APC/C complex and targeted to proteasomal degradation. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are ubiquitinated by WWP1. The ERBB4 intracellular domain (E4ICD1) is ubiquitinated, and this involves NEDD4.2 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ15303.
PaxDbiQ15303.
PeptideAtlasiQ15303.
PRIDEiQ15303.

PTM databases

iPTMnetiQ15303.
PhosphoSiteiQ15303.

Miscellaneous databases

PMAP-CutDBQ15303.

Expressioni

Tissue specificityi

Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are expressed in cerebellum, but only the isoform JM-B is expressed in the heart.3 Publications

Gene expression databases

BgeeiENSG00000178568.
CleanExiHS_ERBB4.
ExpressionAtlasiQ15303. baseline and differential.
GenevisibleiQ15303. HS.

Organism-specific databases

HPAiCAB000276.
CAB025522.
HPA012016.

Interactioni

Subunit structurei

Monomer in the absence of bound ligand. Homodimer or heterodimer with another ERBB family member upon ligand binding, thus forming heterotetramers. Interacts with EGFR and ERBB2. Interacts with CBFA2T3 (By similarity). Interacts with DLG2 (via its PDZ domain), DLG3 (via its PDZ domain), DLG4 (via its PDZ domain) and SNTB2 (via its PDZ domain). Interacts with MUC1. Interacts (via its PPxy motifs) with WWOX. Interacts (via the PPxY motif 3 of isoform JM-A CYT-2) with YAP1 (via the WW domain 1 of isoform 1). Interacts (isoform JM-A CYT-1 and isoform JM-B CYT-1) with WWP1. Interacts (via its intracellular domain) with TRIM28. Interacts (via the intracellular domains of both CYT-1 and CYT-2 isoforms) with KAP1; the interaction does not phosphorylate KAP1 but represses ERBB4-mediated transcriptional activity. Interacts with PRPU, DDX23, MATR3, RBM15, ILF3, KAP1, U5S1, U2SURP, ITCH, HNRPU, AP2A1, NULC, LEO1, WWP2, IGHG1, HXK1, GRB7 AND ARS2. Interacts (phosphorylated isoform JM-A CYT-1 and isoform JM-B CYT-1) with PIK3R1. Interacts with SHC1. Interacts with GRB2. Interacts (soluble intracellular domain) with STAT5A. Interacts (soluble intracellular domain) with BCL2. Interacts (phosphorylated) with STAT1.By similarity29 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
ABL2P426844EBI-80371,EBI-1102694
DLG4P783526EBI-80371,EBI-80389
EGFRP005332EBI-80371,EBI-297353
ERBB2P046263EBI-80371,EBI-641062
ERBB3P218604EBI-80371,EBI-720706
HSP90AB1P082382EBI-80371,EBI-352572
SHC1P293532EBI-80371,EBI-78835
YAP1P469373EBI-80371,EBI-1044059

GO - Molecular functioni

  • epidermal growth factor receptor binding Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB

Protein-protein interaction databases

BioGridi108378. 49 interactions.
DIPiDIP-29650N.
IntActiQ15303. 25 interactions.
MINTiMINT-125091.
STRINGi9606.ENSP00000342235.

Chemistry

BindingDBiQ15303.

Structurei

Secondary structure

1
1308
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi28 – 303Combined sources
Beta strandi38 – 414Combined sources
Helixi42 – 5312Combined sources
Beta strandi57 – 615Combined sources
Beta strandi63 – 675Combined sources
Helixi75 – 795Combined sources
Beta strandi82 – 854Combined sources
Beta strandi87 – 915Combined sources
Beta strandi95 – 984Combined sources
Turni112 – 1143Combined sources
Beta strandi115 – 1206Combined sources
Beta strandi125 – 1284Combined sources
Beta strandi133 – 1353Combined sources
Beta strandi144 – 1507Combined sources
Helixi158 – 1603Combined sources
Helixi163 – 1653Combined sources
Helixi173 – 1753Combined sources
Beta strandi176 – 1783Combined sources
Turni191 – 1933Combined sources
Beta strandi197 – 2015Combined sources
Helixi202 – 2043Combined sources
Beta strandi221 – 2255Combined sources
Helixi226 – 2283Combined sources
Beta strandi234 – 2429Combined sources
Beta strandi245 – 25410Combined sources
Beta strandi257 – 2615Combined sources
Beta strandi265 – 2695Combined sources
Turni270 – 2734Combined sources
Beta strandi274 – 2774Combined sources
Beta strandi283 – 2853Combined sources
Beta strandi288 – 2925Combined sources
Beta strandi298 – 3003Combined sources
Beta strandi303 – 3075Combined sources
Beta strandi312 – 3176Combined sources
Beta strandi320 – 3256Combined sources
Beta strandi327 – 3293Combined sources
Beta strandi333 – 3353Combined sources
Helixi340 – 3423Combined sources
Turni350 – 3523Combined sources
Helixi353 – 3564Combined sources
Beta strandi360 – 3645Combined sources
Beta strandi366 – 3683Combined sources
Helixi370 – 3745Combined sources
Helixi377 – 3793Combined sources
Helixi386 – 3949Combined sources
Beta strandi397 – 4004Combined sources
Beta strandi402 – 4054Combined sources
Helixi415 – 4173Combined sources
Beta strandi432 – 4387Combined sources
Beta strandi455 – 4617Combined sources
Helixi469 – 4713Combined sources
Helixi474 – 4763Combined sources
Beta strandi479 – 4824Combined sources
Beta strandi485 – 4873Combined sources
Beta strandi489 – 4913Combined sources
Helixi493 – 4975Combined sources
Turni498 – 5003Combined sources
Beta strandi512 – 5165Combined sources
Beta strandi519 – 52810Combined sources
Beta strandi531 – 5344Combined sources
Beta strandi537 – 5437Combined sources
Beta strandi545 – 5484Combined sources
Beta strandi551 – 5544Combined sources
Beta strandi568 – 5736Combined sources
Beta strandi576 – 58510Combined sources
Beta strandi588 – 5925Combined sources
Beta strandi595 – 60814Combined sources
Beta strandi612 – 6165Combined sources
Beta strandi625 – 6295Combined sources
Helixi651 – 67626Combined sources
Helixi715 – 7173Combined sources
Beta strandi718 – 72912Combined sources
Beta strandi731 – 7377Combined sources
Beta strandi740 – 7434Combined sources
Beta strandi746 – 7527Combined sources
Helixi762 – 77312Combined sources
Beta strandi778 – 7803Combined sources
Beta strandi783 – 7875Combined sources
Beta strandi789 – 7913Combined sources
Beta strandi793 – 7975Combined sources
Helixi804 – 8107Combined sources
Helixi812 – 8143Combined sources
Helixi817 – 83620Combined sources
Helixi846 – 8483Combined sources
Beta strandi849 – 8535Combined sources
Beta strandi856 – 8594Combined sources
Helixi864 – 8696Combined sources
Helixi884 – 8863Combined sources
Helixi889 – 8935Combined sources
Helixi899 – 91416Combined sources
Turni920 – 9234Combined sources
Turni926 – 9283Combined sources
Helixi929 – 9346Combined sources
Helixi947 – 9559Combined sources
Helixi961 – 9633Combined sources
Helixi967 – 97711Combined sources
Helixi981 – 9833Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2AHXX-ray2.40A/B26-641[»]
2L2TNMR-A/B642-685[»]
2LCXNMR-A/B642-685[»]
2R4BX-ray2.40A/B690-999[»]
3BBTX-ray2.80B/D702-1029[»]
3BBWX-ray4.00A/B702-1029[»]
3BCEX-ray2.50A/B/C702-1029[»]
3U2PX-ray2.57A26-522[»]
3U7UX-ray3.03A/B/C/D/E/F26-640[»]
3U9UX-ray3.42E/F26-650[»]
ProteinModelPortaliQ15303.
SMRiQ15303. Positions 26-639, 642-1026.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ15303.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini718 – 985268Protein kinasePROSITE-ProRule annotationAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi676 – 6849Nuclear localization signal
Motifi1032 – 10354PPxY motif 1
Motifi1053 – 10564PPxY motif 2
Motifi1298 – 13014PPxY motif 3
Motifi1306 – 13083PDZ-binding

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi186 – 334149Cys-richAdd
BLAST
Compositional biasi496 – 633138Cys-richAdd
BLAST

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1025. Eukaryota.
ENOG410XNSR. LUCA.
GeneTreeiENSGT00760000118799.
HOGENOMiHOG000230982.
HOVERGENiHBG000490.
InParanoidiQ15303.
KOiK05085.
OMAiRTRIDSN.
OrthoDBiEOG091G00EY.
PhylomeDBiQ15303.
TreeFamiTF106002.

Family and domain databases

Gene3Di3.80.20.20. 2 hits.
InterProiIPR006211. Furin-like_Cys-rich_dom.
IPR006212. Furin_repeat.
IPR032778. GF_recep_IV.
IPR009030. Growth_fac_rcpt_.
IPR011009. Kinase-like_dom.
IPR032675. L_dom-like.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR000494. Rcpt_L-dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR016245. Tyr_kinase_EGF/ERB/XmrK_rcpt.
[Graphical view]
PfamiPF00757. Furin-like. 1 hit.
PF14843. GF_recep_IV. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF01030. Recep_L_domain. 2 hits.
[Graphical view]
PIRSFiPIRSF000619. TyrPK_EGF-R. 1 hit.
PRINTSiPR00109. TYRKINASE.
SMARTiSM00261. FU. 5 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF52058. SSF52058. 2 hits.
SSF56112. SSF56112. 1 hit.
SSF57184. SSF57184. 2 hits.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
[Graphical view]

Sequences (4)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform JM-A CYT-1 (identifier: Q15303-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MKPATGLWVW VSLLVAAGTV QPSDSQSVCA GTENKLSSLS DLEQQYRALR
60 70 80 90 100
KYYENCEVVM GNLEITSIEH NRDLSFLRSV REVTGYVLVA LNQFRYLPLE
110 120 130 140 150
NLRIIRGTKL YEDRYALAIF LNYRKDGNFG LQELGLKNLT EILNGGVYVD
160 170 180 190 200
QNKFLCYADT IHWQDIVRNP WPSNLTLVST NGSSGCGRCH KSCTGRCWGP
210 220 230 240 250
TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG PKDTDCFACM
260 270 280 290 300
NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD
310 320 330 340 350
SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS
360 370 380 390 400
SNIDKFINCT KINGNLIFLV TGIHGDPYNA IEAIDPEKLN VFRTVREITG
410 420 430 440 450
FLNIQSWPPN MTDFSVFSNL VTIGGRVLYS GLSLLILKQQ GITSLQFQSL
460 470 480 490 500
KEISAGNIYI TDNSNLCYYH TINWTTLFST INQRIVIRDN RKAENCTAEG
510 520 530 540 550
MVCNHLCSSD GCWGPGPDQC LSCRRFSRGR ICIESCNLYD GEFREFENGS
560 570 580 590 600
ICVECDPQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA
610 620 630 640 650
NSFIFKYADP DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART
660 670 680 690 700
PLIAAGVIGG LFILVIVGLT FAVYVRRKSI KKKRALRRFL ETELVEPLTP
710 720 730 740 750
SGTAPNQAQL RILKETELKR VKVLGSGAFG TVYKGIWVPE GETVKIPVAI
760 770 780 790 800
KILNETTGPK ANVEFMDEAL IMASMDHPHL VRLLGVCLSP TIQLVTQLMP
810 820 830 840 850
HGCLLEYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV HRDLAARNVL
860 870 880 890 900
VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ
910 920 930 940 950
SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY
960 970 980 990 1000
MVMVKCWMID ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND
1010 1020 1030 1040 1050
SKFFQNLLDE EDLEDMMDAE EYLVPQAFNI PPPIYTSRAR IDSNRSEIGH
1060 1070 1080 1090 1100
SPPPAYTPMS GNQFVYRDGG FAAEQGVSVP YRAPTSTIPE APVAQGATAE
1110 1120 1130 1140 1150
IFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERS PRGELDEEGY
1160 1170 1180 1190 1200
MTPMRDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHN ASNGPPKAED
1210 1220 1230 1240 1250
EYVNEPLYLN TFANTLGKAE YLKNNILSMP EKAKKAFDNP DYWNHSLPPR
1260 1270 1280 1290 1300
STLQHPDYLQ EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTVLPPPP

YRHRNTVV
Note: Proteolytical processing generates E4ICD1 (s80Cyt1).
Length:1,308
Mass (Da):146,808
Last modified:November 1, 1996 - v1
Checksum:i5E4AE80985D88761
GO
Isoform JM-B CYT-1 (identifier: Q15303-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     626-648: NGPTSHDCIYYPWTGHSTLPQHA → IGSSIEDCIGLMD

Show »
Length:1,298
Mass (Da):145,578
Checksum:i346C1288AD041961
GO
Isoform JM-A CYT-2 (identifier: Q15303-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1046-1061: Missing.

Note: Proteolytical processing generates E4ICD2 (s80Cyt2).
Show »
Length:1,292
Mass (Da):145,198
Checksum:i60C0DFD446C7FA89
GO
Isoform JM-B CYT-2 (identifier: Q15303-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     626-648: NGPTSHDCIYYPWTGHSTLPQHA → IGSSIEDCIGLMD
     1046-1061: Missing.

Show »
Length:1,282
Mass (Da):143,968
Checksum:i68F27777BC9E2F74
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti140 – 1401T → I in a colorectal adenocarcinoma sample; somatic mutation. 1 Publication
VAR_042113
Natural varianti303 – 3031S → Y in a lung squamous cell carcinoma sample; somatic mutation. 1 Publication
VAR_042114
Natural varianti927 – 9271R → Q in ALS19; reduces autophosphorylation upon NRG1 stimulation. 1 Publication
Corresponds to variant rs397514262 [ dbSNP | Ensembl ].
VAR_070810
Natural varianti1275 – 12751R → W in ALS19; reduces autophosphorylation upon NRG1 stimulation. 1 Publication
Corresponds to variant rs397514263 [ dbSNP | Ensembl ].
VAR_070811

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei626 – 64823NGPTS…LPQHA → IGSSIEDCIGLMD in isoform JM-B CYT-1 and isoform JM-B CYT-2. 2 PublicationsVSP_002895Add
BLAST
Alternative sequencei1046 – 106116Missing in isoform JM-A CYT-2 and isoform JM-B CYT-2. 2 PublicationsVSP_022148Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L07868 mRNA. Translation: AAB59446.1.
BC112199 mRNA. Translation: AAI12200.1.
BC143741 mRNA. Translation: AAI43742.1.
BC143747 mRNA. Translation: AAI43748.1.
BC143749 mRNA. Translation: AAI43750.1.
AB209697 mRNA. Translation: BAD92934.1.
CCDSiCCDS2394.1. [Q15303-1]
CCDS42811.1. [Q15303-3]
PIRiA47253.
RefSeqiNP_001036064.1. NM_001042599.1. [Q15303-3]
NP_005226.1. NM_005235.2. [Q15303-1]
XP_005246433.1. XM_005246376.2. [Q15303-2]
XP_005246434.1. XM_005246377.2. [Q15303-4]
UniGeneiHs.390729.

Genome annotation databases

EnsembliENST00000342788; ENSP00000342235; ENSG00000178568. [Q15303-1]
ENST00000436443; ENSP00000403204; ENSG00000178568. [Q15303-3]
GeneIDi2066.
KEGGihsa:2066.
UCSCiuc002veg.2. human. [Q15303-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L07868 mRNA. Translation: AAB59446.1.
BC112199 mRNA. Translation: AAI12200.1.
BC143741 mRNA. Translation: AAI43742.1.
BC143747 mRNA. Translation: AAI43748.1.
BC143749 mRNA. Translation: AAI43750.1.
AB209697 mRNA. Translation: BAD92934.1.
CCDSiCCDS2394.1. [Q15303-1]
CCDS42811.1. [Q15303-3]
PIRiA47253.
RefSeqiNP_001036064.1. NM_001042599.1. [Q15303-3]
NP_005226.1. NM_005235.2. [Q15303-1]
XP_005246433.1. XM_005246376.2. [Q15303-2]
XP_005246434.1. XM_005246377.2. [Q15303-4]
UniGeneiHs.390729.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2AHXX-ray2.40A/B26-641[»]
2L2TNMR-A/B642-685[»]
2LCXNMR-A/B642-685[»]
2R4BX-ray2.40A/B690-999[»]
3BBTX-ray2.80B/D702-1029[»]
3BBWX-ray4.00A/B702-1029[»]
3BCEX-ray2.50A/B/C702-1029[»]
3U2PX-ray2.57A26-522[»]
3U7UX-ray3.03A/B/C/D/E/F26-640[»]
3U9UX-ray3.42E/F26-650[»]
ProteinModelPortaliQ15303.
SMRiQ15303. Positions 26-639, 642-1026.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi108378. 49 interactions.
DIPiDIP-29650N.
IntActiQ15303. 25 interactions.
MINTiMINT-125091.
STRINGi9606.ENSP00000342235.

Chemistry

BindingDBiQ15303.
ChEMBLiCHEMBL2363049.
DrugBankiDB08916. Afatinib.
GuidetoPHARMACOLOGYi1799.

Protein family/group databases

TCDBi1.A.87.2.6. the mechanosensitive calcium channel (mca) family.

PTM databases

iPTMnetiQ15303.
PhosphoSiteiQ15303.

Polymorphism and mutation databases

BioMutaiERBB4.
DMDMi3913590.

Proteomic databases

MaxQBiQ15303.
PaxDbiQ15303.
PeptideAtlasiQ15303.
PRIDEiQ15303.

Protocols and materials databases

DNASUi2066.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000342788; ENSP00000342235; ENSG00000178568. [Q15303-1]
ENST00000436443; ENSP00000403204; ENSG00000178568. [Q15303-3]
GeneIDi2066.
KEGGihsa:2066.
UCSCiuc002veg.2. human. [Q15303-1]

Organism-specific databases

CTDi2066.
GeneCardsiERBB4.
HGNCiHGNC:3432. ERBB4.
HPAiCAB000276.
CAB025522.
HPA012016.
MalaCardsiERBB4.
MIMi600543. gene.
615515. phenotype.
neXtProtiNX_Q15303.
Orphaneti803. Amyotrophic lateral sclerosis.
PharmGKBiPA27847.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1025. Eukaryota.
ENOG410XNSR. LUCA.
GeneTreeiENSGT00760000118799.
HOGENOMiHOG000230982.
HOVERGENiHBG000490.
InParanoidiQ15303.
KOiK05085.
OMAiRTRIDSN.
OrthoDBiEOG091G00EY.
PhylomeDBiQ15303.
TreeFamiTF106002.

Enzyme and pathway databases

BRENDAi2.7.10.1. 2681.
ReactomeiR-HSA-1227986. Signaling by ERBB2.
R-HSA-1236394. Signaling by ERBB4.
R-HSA-1250196. SHC1 events in ERBB2 signaling.
R-HSA-1250342. PI3K events in ERBB4 signaling.
R-HSA-1250347. SHC1 events in ERBB4 signaling.
R-HSA-1251985. Nuclear signaling by ERBB4.
R-HSA-1253288. Downregulation of ERBB4 signaling.
R-HSA-1257604. PIP3 activates AKT signaling.
R-HSA-1963640. GRB2 events in ERBB2 signaling.
R-HSA-1963642. PI3K events in ERBB2 signaling.
R-HSA-2219530. Constitutive Signaling by Aberrant PI3K in Cancer.
R-HSA-5673001. RAF/MAP kinase cascade.
R-HSA-6785631. ERBB2 Regulates Cell Motility.
R-HSA-6811558. PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
R-HSA-8847993. ERBB2 Activates PTK6 Signaling.
SignaLinkiQ15303.
SIGNORiQ15303.

Miscellaneous databases

ChiTaRSiERBB4. human.
EvolutionaryTraceiQ15303.
GeneWikiiERBB4.
GenomeRNAii2066.
PMAP-CutDBQ15303.
PROiQ15303.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000178568.
CleanExiHS_ERBB4.
ExpressionAtlasiQ15303. baseline and differential.
GenevisibleiQ15303. HS.

Family and domain databases

Gene3Di3.80.20.20. 2 hits.
InterProiIPR006211. Furin-like_Cys-rich_dom.
IPR006212. Furin_repeat.
IPR032778. GF_recep_IV.
IPR009030. Growth_fac_rcpt_.
IPR011009. Kinase-like_dom.
IPR032675. L_dom-like.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR000494. Rcpt_L-dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR016245. Tyr_kinase_EGF/ERB/XmrK_rcpt.
[Graphical view]
PfamiPF00757. Furin-like. 1 hit.
PF14843. GF_recep_IV. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF01030. Recep_L_domain. 2 hits.
[Graphical view]
PIRSFiPIRSF000619. TyrPK_EGF-R. 1 hit.
PRINTSiPR00109. TYRKINASE.
SMARTiSM00261. FU. 5 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF52058. SSF52058. 2 hits.
SSF56112. SSF56112. 1 hit.
SSF57184. SSF57184. 2 hits.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiERBB4_HUMAN
AccessioniPrimary (citable) accession number: Q15303
Secondary accession number(s): B7ZLD7
, B7ZLE2, B7ZLE3, Q2M1W1, Q59EW4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: November 1, 1996
Last modified: September 7, 2016
This is version 188 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Caution

Conflicting reports about the role of ERBB4 in mediating apoptosis, differentiation, or tumor cell proliferation may be explained by the opposite functions of the different isoforms and their intracellular fragments, and by the formation of heterodimers with other EGF receptor family members (PubMed:18454307 and PubMed:21811097). Thus, heterodimer formation of a kinase-dead ERBB4 mutant with ERBB2 is sufficient for the activation of AKT1, MAPK1/ERK2 and MAPK3/ERK1 (PubMed:19098003).1 Publication

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.