Protein:ERBB4 |
Protein Summary |
 Gene summary |
| Gene name: ERBB4 | ASpdb.0 ID: 2066 | Gene | Gene symbol | ERBB4 | Gene ID | 2066 |
| Gene name | erb-b2 receptor tyrosine kinase 4 |
| Synonyms | ALS19|HER4|p180erbB4 |
| Cytomap | 2q34 |
| Type of gene | protein-coding |
| Description | receptor tyrosine-protein kinase erbB-4avian erythroblastic leukemia viral (v-erb-b2) oncogene homolog 4human epidermal growth factor receptor 4proto-oncogene-like protein c-ErbB-4tyrosine kinase-type cell surface receptor HER4v-erb-a erythroblastic |
| Modification date | 20240411 |
| UniProtAcc | Q15303 |
| Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez |
| Partner | Gene | GO ID | GO term | PubMed ID |
| Gene | ERBB4 | GO:0004713 | protein tyrosine kinase activity | 18334220 |
| Gene | ERBB4 | GO:0004714 | transmembrane receptor protein tyrosine kinase activity | 18334220 |
| Gene | ERBB4 | GO:0005634 | nucleus | 15534001 |
| Gene | ERBB4 | GO:0005739 | mitochondrion | 16778220 |
| Gene | ERBB4 | GO:0005886 | plasma membrane | 9275162|12466964 |
| Gene | ERBB4 | GO:0007165 | signal transduction | 10572067 |
| Gene | ERBB4 | GO:0007169 | cell surface receptor protein tyrosine kinase signaling pathway | 10353604|18334220 |
| Gene | ERBB4 | GO:0016323 | basolateral plasma membrane | 12646923 |
| Gene | ERBB4 | GO:0016477 | cell migration | 9135143 |
| Gene | ERBB4 | GO:0018108 | peptidyl-tyrosine phosphorylation | 18334220 |
| Gene | ERBB4 | GO:0038130 | ERBB4 signaling pathway | 9275162|12466964 |
| Gene | ERBB4 | GO:0038131 | neuregulin receptor activity | 9275162|12466964 |
| Gene | ERBB4 | GO:0038138 | ERBB4-ERBB4 signaling pathway | 9275162|12466964 |
| Gene | ERBB4 | GO:0043235 | receptor complex | 23382219 |
| Gene | ERBB4 | GO:0046777 | protein autophosphorylation | 18334220 |
AS Summary |
| Information of the canonical protein with experimentally identified structure from PDB (2023). |
| UniProt Acc | File name | PDB ID | Method | Resolution | Chain | Start | End |
| Q15303-1 | Q15303-1_2ahx_A.pdb | 2AHX | X-ray | 2.4 | A | 26 | 641 |
| ASpdb's canonical and alternatively spliced isoform information. |
| accession_id | gene_name | canonical_id | alternative_id | canonical_length | alternative_length | canonical_start | canonical_end | type | originalSEQ | variationSEQ | alternative_start | alternative_end |
| Q15303 | ERBB4 | Q15303-1 | Q15303-3 | 1308 | 1292 | 1046 | 1061 | Deletion | none | none | 1045 | 1045 |
| Multiple sequence alignment of our canonical and alternatively spliced ERBB4 |
| Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of ERBB4 |
| UniProt-id | ENSG | ENST | ENSP |
| Q15303-1 | ENSG00000178568.16 | ENST00000342788.9 | ENSP00000342235.4 |
| Q15303-3 | ENSG00000178568.16 | ENST00000436443.5 | ENSP00000403204.1 |
| UniProt-id | NM ID | NP ID |
| Q15303-1 | NM_005235.2 | NP_005226.1 |
| Q15303-3 | NM_001042599.1 | NP_001036064.1 |
| Amino acid sequences of our canonical and alternatively spliced ERBB4 |
| accession_id | Protein sequence |
| Q15303-1 | MKPATGLWVWVSLLVAAGTVQPSDSQSVCAGTENKLSSLSDLEQQYRALRKYYENCEVVMGNLEITSIEHNRDLSFLRSVREVTGYVLVA LNQFRYLPLENLRIIRGTKLYEDRYALAIFLNYRKDGNFGLQELGLKNLTEILNGGVYVDQNKFLCYADTIHWQDIVRNPWPSNLTLVST NGSSGCGRCHKSCTGRCWGPTENHCQTLTRTVCAEQCDGRCYGPYVSDCCHRECAGGCSGPKDTDCFACMNFNDSGACVTQCPQTFVYNP TTFQLEHNFNAKYTYGAFCVKKCPHNFVVDSSSCVRACPSSKMEVEENGIKMCKPCTDICPKACDGIGTGSLMSAQTVDSSNIDKFINCT KINGNLIFLVTGIHGDPYNAIEAIDPEKLNVFRTVREITGFLNIQSWPPNMTDFSVFSNLVTIGGRVLYSGLSLLILKQQGITSLQFQSL KEISAGNIYITDNSNLCYYHTINWTTLFSTINQRIVIRDNRKAENCTAEGMVCNHLCSSDGCWGPGPDQCLSCRRFSRGRICIESCNLYD GEFREFENGSICVECDPQCEKMEDGLLTCHGPGPDNCTKCSHFKDGPNCVEKCPDGLQGANSFIFKYADPDRECHPCHPNCTQGCNGPTS HDCIYYPWTGHSTLPQHARTPLIAAGVIGGLFILVIVGLTFAVYVRRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKR VKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSPTIQLVTQLMPHGCLLEYVHE HKDNIGSQLLLNWCVQIAKGMMYLEERRLVHRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKFTHQ SDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCWMIDADSRPKFKELAAEFSRMARDPQRYLVIQGD DRMKLPSPNDSKFFQNLLDEEDLEDMMDAEEYLVPQAFNIPPPIYTSRARIDSNRSEIGHSPPPAYTPMSGNQFVYRDGGFAAEQGVSVP YRAPTSTIPEAPVAQGATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYSADPTVFAPERSPRGELDEEGYMTPMRDKPKQEYLNPVEENP FVSRRKNGDLQALDNPEYHNASNGPPKAEDEYVNEPLYLNTFANTLGKAEYLKNNILSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQ |
| Q15303-3 | MKPATGLWVWVSLLVAAGTVQPSDSQSVCAGTENKLSSLSDLEQQYRALRKYYENCEVVMGNLEITSIEHNRDLSFLRSVREVTGYVLVA LNQFRYLPLENLRIIRGTKLYEDRYALAIFLNYRKDGNFGLQELGLKNLTEILNGGVYVDQNKFLCYADTIHWQDIVRNPWPSNLTLVST NGSSGCGRCHKSCTGRCWGPTENHCQTLTRTVCAEQCDGRCYGPYVSDCCHRECAGGCSGPKDTDCFACMNFNDSGACVTQCPQTFVYNP TTFQLEHNFNAKYTYGAFCVKKCPHNFVVDSSSCVRACPSSKMEVEENGIKMCKPCTDICPKACDGIGTGSLMSAQTVDSSNIDKFINCT KINGNLIFLVTGIHGDPYNAIEAIDPEKLNVFRTVREITGFLNIQSWPPNMTDFSVFSNLVTIGGRVLYSGLSLLILKQQGITSLQFQSL KEISAGNIYITDNSNLCYYHTINWTTLFSTINQRIVIRDNRKAENCTAEGMVCNHLCSSDGCWGPGPDQCLSCRRFSRGRICIESCNLYD GEFREFENGSICVECDPQCEKMEDGLLTCHGPGPDNCTKCSHFKDGPNCVEKCPDGLQGANSFIFKYADPDRECHPCHPNCTQGCNGPTS HDCIYYPWTGHSTLPQHARTPLIAAGVIGGLFILVIVGLTFAVYVRRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKR VKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSPTIQLVTQLMPHGCLLEYVHE HKDNIGSQLLLNWCVQIAKGMMYLEERRLVHRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKFTHQ SDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCWMIDADSRPKFKELAAEFSRMARDPQRYLVIQGD DRMKLPSPNDSKFFQNLLDEEDLEDMMDAEEYLVPQAFNIPPPIYTSRARIDSNRNQFVYRDGGFAAEQGVSVPYRAPTSTIPEAPVAQG ATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYSADPTVFAPERSPRGELDEEGYMTPMRDKPKQEYLNPVEENPFVSRRKNGDLQALDNP EYHNASNGPPKAEDEYVNEPLYLNTFANTLGKAEYLKNNILSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQEYSTKYFYKQNGRIRP |
Protein Functional Features |
| Main function of this protein. (from UniProt) |
| ERBB4 (go to UniProt):Q15303 |
| Retention analysis result of protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, because of limited space for viewing, we only show the protein feature retention information belong to the 13 regional features. All retention annotation result can be downloaded at * Minus value of BPloci means that the break pointn is located before the CDS. |
| - Retained protein feature among the 13 regional features. |
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| Q15303 | Topological domain | 676 | 1308 | Note=Cytoplasmic;Ontology_term=ECO:0000255;evidence=ECO:0000255 | Type=Deletion;Start=1046;End=1061 |
| Q15303 | Motif | 1053 | 1056 | Note=PPxY motif 2 | Type=Deletion;Start=1046;End=1061 |
Gene Isoform Structures and Expression Levels for ERBB4 |
| Gene structures of our canonical and alternative spliced genes of ERBB4 * Click on the image to open the UCSC genome browser with custom track showing this image in a new window. |
| Expression levels of gene isoforms across GTEx. |
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| Expression levels of gene isoforms across TCGA. |
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Protein Structures |
| PDB and CIF files of the predicted protein structures * Here we show the 3D structure of the proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format. |
| 3D view using mol* of Q15303-1 |
| 3D view using mol* of Q15303-3 |
pLDDT Score Distribution |
| pLDDT score distribution of the predicted protein structures from AlphaFold2 * AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. |
| pLDDT distribution across the protein length of Q15303-1 |
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| pLDDT distribution across the protein length of Q15303-3 |
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Ramachandran Plot of Protein Structures |
| Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this protein peptide. |
| Ramachandran plot of Q15303-1 |
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| Ramachandran plot of Q15303-3 |
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Potential Active Site Information |
| The potential binding sites of these proteins were identified using SiteMap, a module of the Schrodinger suite. |
| UniProt-id | Site score | Size | D score | Volume | Exposure | Enclosure | Contact | Phobic | Philic | Balance | Don/Acc | Residues |
| Q15303-1 | 1.113 | 127 | 1.146 | 431.837 | 0.517 | 0.821 | 1.057 | 1.345 | 0.879 | 1.53 | 1.176 | 724,725,726,727,728,729,730,731,732,749,751,768,77 2,781,794,796,798,799,801,802,803,806,807,810,811, 843,847,848,850,860,861,862,1001,1003,1284 |
| Q15303-3 | 1.113 | 140 | 1.166 | 508.669 | 0.577 | 0.783 | 0.971 | 1.13 | 0.746 | 1.513 | 1.964 | 722,724,725,726,727,728,729,730,732,749,751,768,77 2,781,794,796,798,799,801,802,803,806,807,810,811, 847,848,850,860,861,1001,1002,1003,1006,1007 |
Protein Structure and Feature Comparision |
| Protein Structure Comparision Using Template Modeling Scores (TM-score). |
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| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Canonical validated structure (PDB)(green) |
| 3D view using mol* of Q15303-1_Q15303-1_2ahx_A.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical validated structure (PDB)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of Q15303-1_2ahx_A_Q15303-3.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of Q15303-1_Q15303-3.pdb |
| Protein Feature Comparison of the protein sequendary structures among the protiens. |
| ./stats/secondary_structure/figure/Q15303-1_vs_Q15303-3.png |
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| Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens. |
| ./stats/relative_asa/Q15303-1_vs_Q15303-3.png |
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Protein-Protein Interaction |
| Interactors from UniProt. |
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| Interactors from STRING. |
| Gene name | Interactors |
Related Drugs to ERBB4 |
| Drugs targeting this gene/protein. (DrugBank) |
| UniProt accession | Gene name | DrugBank ID | Drug name | Drug group | Actions |
| Q15303 | ERBB4 | DB15035 | Zanubrutinib | approved, investigational | inhibitor |
| Q15303 | ERBB4 | DB12267 | Brigatinib | approved, investigational | inhibitor |
| Q15303 | ERBB4 | DB12010 | Fostamatinib | approved, investigational | inhibitor |
| Q15303 | ERBB4 | DB08916 | Afatinib | approved | inhibitor |
Related Diseases to ERBB4 |
| Previous studies relating to the alternative splicing of ERBB4 and disease information from the MeSH term (PubMed) |
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| ERBB4 | 16878160 | Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets. | Medulloblastoma (MB) results from aberrant development of cerebellar neurons in which altered hedgehog (Hh) signalling plays a major role. We investigated the possible influence of Hh signalling on ErbB-receptor expression in MB, in particular that of the ErbB-4 CYT-1 and CYT-2 isoforms generated by alternative splicing of the cytoplasmic domain. ErbB-4 expression was downregulated in Hh-induced MBs from Patched-1(+/-) mice. Hh signalling (reflected by enhanced expression of the Gli1 transcription factor) inhibited ErbB-4 expression in mouse cerebellar granule progenitors and human MB cells. Analysis of 26 human primary MBs revealed a subset of 11 tumors characterized by low Gli1 levels, upregulated ErbB-4 expression and increased CYT-1:CYT-2 ratios. Interestingly, CYT-1 and Gli1 levels were inversely correlated. ErbB-4 CYT-1 and CYT-2 had different phenotypic effects in cultured MB cells: in response to neuregulin treatment, CYT-2 overexpression inhibited proliferation whereas CYT-1, which includes a phosphatidylinositol 3-kinase (PI3K)-binding site that is missing in CYT-2, enhanced resistance to starvation- and etoposide-induced apoptosis by activating PI3K/Akt signalling. CYT-1:CYT-2 ratios displayed correlation with tumor histotype and ErbB-2 levels, which are established prognostic indices for MB. These findings demonstrate that low-level Hh signalling in human MB is associated with the selective maintenance of high ErbB-4 CYT-1 expression, an alteration that exerts tumor-promoting effects. | D008527 | Medulloblastoma |
| ERBB4 | 17164265 | Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia. | The neuregulin 1 (NRG1) receptor, ErbB4, has been identified as a potential risk gene for schizophrenia. HER4/ErbB4 is a receptor tyrosine kinase whose transcript undergoes alternative splicing in the brain. Exon 16 encodes isoforms containing a metalloprotease cleavable extracellular domain (JM-a), exon 15 for a cleavage resistant form (JM-b) and exon 26 for a cytoplasmic domain (CYT-1) with a phosphotidylinositol-3 kinase (PI3K) binding site. Disease-associated variants in the ErbB4 gene are intronic and implicate altered splicing of the gene. We examined ErbB4 splice-variant gene expression in the hippocampus and dorsolateral prefrontal cortex (DLPFC) in schizophrenia using qPCR and investigated whether expression levels are associated with previously reported genomic risk variants in ErbB4 in a large cohort of human brains. In the DLPFC, we confirmed previous observations, in a separate cohort, that mRNA for ErbB4 splice isoforms containing exon 16 (JM-a) and exon 26 (CYT-1) are significantly elevated in patients with schizophrenia. A main effect of genotype was observed in the DLPFC and hippocampus at a single risk SNP located in intron 12 (rs4673628) on isoforms containing exon 16 (JM-a). We also found that three intronic risk SNPs (rs7598440, rs707284, rs839523) and a core-risk haplotype surrounding exon 3 are strongly associated with elevated expression of splice variants containing exon 26 (CYT-1). These findings suggest that dysregulation of splice-variant specific expression of ErbB4 in the brain underlies the genetic association of the gene with schizophrenia and that the NRG1/ErbB4 signaling pathway may be an important genetic network involved in the pathogenesis of the disease. | D020022 | Genetic Predisposition to Disease |
| ERBB4 | 21637803 | Exonic DNA sequencing of ERBB4 in bipolar disorder. | The Neuregulin-ErbB4 pathway plays a crucial role in brain development and constitutes one of the most biologically plausible signaling pathways implicated in schizophrenia and, to a lesser extent, in bipolar disorder (BP). However, recent genome-wide association analyses have not provided evidence for common variation in NRG1 or ERBB4 influencing schizophrenia or bipolar disorder susceptibility. In this study, we investigate the role of rare coding variants in ERBB4 in BP cases with mood-incongruent psychotic features, a form of BP with arguably the greatest phenotypic overlap with schizophrenia. We performed Sanger sequencing of all 28 exons in ERBB4, as well as part of the promoter and part of the 3'UTR sequence, hypothesizing that rare deleterious variants would be found in 188 cases with mood-incongruent psychosis from the GAIN BP study. We found 42 variants, of which 16 were novel, although none were non-synonymous or clearly deleterious. One of the novel variants, present in 11.2% of cases, is located next to an alternative stop codon, which is associated with a shortened transcript of ERBB4 that is not translated. We genotyped this variant in the GAIN BP case-control samples and found a marginally significant association with mood-incongruent psychotic BP compared with controls (additive model: OR = 1.64, P-value = 0.055; dominant model: OR = 1.73. P-value = 0.039). In conclusion, we found no rare variants of clear deleterious effect, but did uncover a modestly associated novel variant that could affect alternative splicing of ERBB4. However, the modest sample size in this study cannot definitively rule out a role for rare variants in bipolar disorder and studies with larger sample sizes are needed to confirm the observed association. | D020022 | Genetic Predisposition to Disease |
Clinically important variants in ERBB4 |
| (ClinVar, 04/20/2024) |
| accession_id | uniprot_id | gene_name | Type | Variant | Clinical_significance |
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