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Center for Computational Systems Medicine
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Fusion Gene and Fusion Protein Summary

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Fusion Amino Acid Sequences (multiple BPs and multiple gene isoforms)

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Fusion Protein Breakpoint Sequences - (for the Screening of the FusionNeoAntigens)

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Potential FusionNeoAntigens in HLA I - (netMHCpan v4.1 + deepHLApan v1.1)

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Potential FusionNeoAntigens in HLA II - (netMHCIIpan v4.1)

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Fusion Breakpoint 14 AA Peptide Structure - (RoseTTAFold)

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D - (Glide)

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Vaccine Design for the FusionNeoAntigens (RNA/protein sequences)

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Potential target of CAR-T therapy development

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Information on the samples that have these potential fusion neoantigens

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Fusion Protein Targeting Drugs - (Manual Curation)

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Fusion Protein Related diseases - (Manual Curation)

Fusion Protein:TYK2-KEAP1

Fusion Gene and Fusion Protein Summary

check button Fusion gene summary
Fusion partner gene informationFusion gene name: TYK2-KEAP1
FusionPDB ID: 95651
FusionGDB2.0 ID: 95651
HgeneTgene
Gene symbol

TYK2

KEAP1

Gene ID

7297

9817

Gene nametyrosine kinase 2kelch like ECH associated protein 1
SynonymsIMD35|JTK1INrf2|KLHL19
Cytomap

19p13.2

19p13.2

Type of geneprotein-codingprotein-coding
Descriptionnon-receptor tyrosine-protein kinase TYK2kelch-like ECH-associated protein 1KEAP1 delta Ccytosolic inhibitor of Nrf2kelch-like family member 19kelch-like protein 19
Modification date2020032920200327
UniProtAcc.

Q14145

Main function of 5'-partner protein: FUNCTION: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination (PubMed:14585973, PubMed:15379550, PubMed:15572695, PubMed:15983046, PubMed:15601839). KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes (PubMed:15601839, PubMed:16006525). In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (PubMed:19489739, PubMed:16006525, PubMed:17127771, PubMed:18251510, PubMed:29590092). In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2 (PubMed:20452972). The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation (PubMed:28380357). The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome (PubMed:15379550, PubMed:17046835). {ECO:0000269|PubMed:14585973, ECO:0000269|PubMed:15379550, ECO:0000269|PubMed:15572695, ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:15983046, ECO:0000269|PubMed:16006525, ECO:0000269|PubMed:17046835, ECO:0000269|PubMed:17127771, ECO:0000269|PubMed:18251510, ECO:0000269|PubMed:19489739, ECO:0000269|PubMed:20452972, ECO:0000269|PubMed:28380357, ECO:0000269|PubMed:29590092}.
Ensembl transtripts involved in fusion geneENST idsENST00000264818, ENST00000524462, 
ENST00000525621, ENST00000529370, 
ENST00000529422, 
ENST00000588024, 
ENST00000171111, ENST00000393623, 
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)* DoF score13 X 11 X 8=11446 X 5 X 5=150
# samples 158
** MAII scorelog2(15/1144*10)=-2.93105264628251
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
log2(8/150*10)=-0.906890595608519
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
Fusion gene context

PubMed: TYK2 [Title/Abstract] AND KEAP1 [Title/Abstract] AND fusion [Title/Abstract]

Fusion neoantigen context

PubMed: TYK2 [Title/Abstract] AND KEAP1 [Title/Abstract] AND neoantigen [Title/Abstract]

Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)TYK2(10490291)-KEAP1(10610756), # samples:2
Anticipated loss of major functional domain due to fusion event.TYK2-KEAP1 seems lost the major protein functional domain in Hgene partner, which is a CGC by not retaining the major functional domain in the partially deleted in-frame ORF.
TYK2-KEAP1 seems lost the major protein functional domain in Hgene partner, which is a essential gene by not retaining the major functional domain in the partially deleted in-frame ORF.
* DoF score (Degree of Frequency) = # partners X # break points X # cancer types
** MAII score (Major Active Isofusion Index) = log2(# samples/DoF score*10)

check button Gene ontology of each fusion partner gene with evidence of Inferred from Direct Assay (IDA) from Entrez
PartnerGeneGO IDGO termPubMed ID
TgeneKEAP1

GO:0006511

ubiquitin-dependent protein catabolic process

15601839

TgeneKEAP1

GO:0010506

regulation of autophagy

20452972

TgeneKEAP1

GO:0016567

protein ubiquitination

15601839|15983046

TgeneKEAP1

GO:0034599

cellular response to oxidative stress

15601839



check button Four levels of functional features of fusion genes
Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr19:10490291/chr19:10610756)
- FGviewer provides the online visualization of the retention search of the protein functional features across DNA, RNA, protein, and pathological levels.
- How to search
1. Put your fusion gene symbol.
2. Press the tab key until there will be shown the breakpoint information filled.
4. Go down and press 'Search' tab twice.
4. Go down to have the hyperlink of the search result.
5. Click the hyperlink.
6. See the FGviewer result for your fusion gene.
FGviewer

check buttonRetention analysis results of each fusion partner 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, are available here.

check buttonFusion gene breakpoints across TYK2 (5'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.
all structure

check buttonFusion gene breakpoints across KEAP1 (3'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.
all structure


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Fusion Amino Acid Sequences


check buttonFusion information from ORFfinder translation from full-length transcript sequence from FusionPDB.
HenstTenstHgeneHchrHbpHstrandTgeneTchrTbpTstrandSeq length
(transcript)
BP loci
(transcript)
Predicted start
(transcript)
Predicted stop
(transcript)
Seq length
(amino acids)
ENST00000264818TYK2chr1910476192-ENST00000171111KEAP1chr1910602938-2779101102246748
ENST00000264818TYK2chr1910476192-ENST00000393623KEAP1chr1910602938-2773101102246748
ENST00000524462TYK2chr1910476192-ENST00000171111KEAP1chr1910602938-2370602381837599
ENST00000524462TYK2chr1910476192-ENST00000393623KEAP1chr1910602938-2364602381837599
ENST00000525621TYK2chr1910476192-ENST00000171111KEAP1chr1910602938-326114934822728748
ENST00000525621TYK2chr1910476192-ENST00000393623KEAP1chr1910602938-325514934822728748
ENST00000529370TYK2chr1910476192-ENST00000171111KEAP1chr1910602938-311013423312577748
ENST00000529370TYK2chr1910476192-ENST00000393623KEAP1chr1910602938-310413423312577748

check buttonDeepORF prediction of the coding potential based on the fusion transcript sequence of in-frame fusion genes. DeepORF is a coding potential classifier based on convolutional neural network by comparing the real Ribo-seq data. If the no-coding score < 0.5 and coding score > 0.5, then the in-frame fusion transcript is predicted as being likely translated.
HenstTenstHgeneHchrHbpHstrandTgeneTchrTbpTstrandNo-coding scoreCoding score
ENST00000264818ENST00000171111TYK2chr1910476192-KEAP1chr1910602938-0.0073277020.9926723
ENST00000264818ENST00000393623TYK2chr1910476192-KEAP1chr1910602938-0.007343790.99265623
ENST00000524462ENST00000171111TYK2chr1910476192-KEAP1chr1910602938-0.0054447410.99455523
ENST00000524462ENST00000393623TYK2chr1910476192-KEAP1chr1910602938-0.0054351880.9945648
ENST00000525621ENST00000171111TYK2chr1910476192-KEAP1chr1910602938-0.0083223320.99167764
ENST00000525621ENST00000393623TYK2chr1910476192-KEAP1chr1910602938-0.0083575690.9916425
ENST00000529370ENST00000171111TYK2chr1910476192-KEAP1chr1910602938-0.0077597290.9922403
ENST00000529370ENST00000393623TYK2chr1910476192-KEAP1chr1910602938-0.0077932550.99220675

check button Predicted full-length fusion amino acid sequences. For individual full-length fusion transcript sequence from FusionPDB, we ran ORFfinder and chose the longest ORF among all the predicted ones.

Get the fusion protein sequences from here.

Fusion protein sequence information is available in the fasta format.
>FusionGDB ID_FusionGDB isoform ID_FGname_Hgene_Hchr_Hbp_Henst_Tgene_Tchr_Tbp_Tenst_length(fusion AA) seq_BP

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Fusion Protein Breakpoint Sequences for TYK2-KEAP1

check button +/-13 AA sequence from the breakpoints of the fusion protein sequences.
HgeneHchrHbpTgeneTchrTbpLength(fusion protein)BP in fusion proteinPeptide
TYK2chr1910476192KEAP1chr19106029381011337QWWPVEEEVNKEEVAKQEEFFNLSHC
TYK2chr1910476192KEAP1chr19106029381342337QWWPVEEEVNKEEVAKQEEFFNLSHC
TYK2chr1910476192KEAP1chr19106029381493337QWWPVEEEVNKEEVAKQEEFFNLSHC
TYK2chr1910476192KEAP1chr1910602938602188QWWPVEEEVNKEEVAKQEEFFNLSHC

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Potential FusionNeoAntigen Information of TYK2-KEAP1 in HLA I

check button Multiple sequence alignments of the potential FusionNeoAntigens per fusion breakpoints. If the MSA is empty, then it means that there were predicted fusion neoantigens in this fusion breakpoint, but those predicted fusion neoantigens were not across the breakpoint, which is not fusion-specific.
TYK2-KEAP1_10476192_10602938.msa

check button Potential FusionNeoAntigen Information
* We used NetMHCpan v4.1 (%rank<0.5) and deepHLApan v1.1 (immunogenic score>0.5)
Fusion geneHchrHbpTgeneTchrTbpHLA IFusionNeoAntigen peptideBinding scoreImmunogenic scoreNeoantigen start (at BP 13)Neoantigen end (at BP 13)
TYK2-KEAP1chr1910476192chr19106029381011HLA-B44:03EEVAKQEEF0.99910.95581120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B45:01EEEVNKEEV0.99680.9428514
TYK2-KEAP1chr1910476192chr19106029381011HLA-B18:01EEVAKQEEF0.99590.83071120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B45:01EEVNKEEVA0.99510.9331615
TYK2-KEAP1chr1910476192chr19106029381011HLA-B50:02EEVNKEEVA0.9920.7216615
TYK2-KEAP1chr1910476192chr19106029381011HLA-B41:01EEVNKEEVA0.61440.9487615
TYK2-KEAP1chr1910476192chr19106029381011HLA-B44:03EEVAKQEEFF0.99750.96161121
TYK2-KEAP1chr1910476192chr19106029381011HLA-B44:03KEEVAKQEEF0.99550.96711020
TYK2-KEAP1chr1910476192chr19106029381011HLA-B45:01EEEVNKEEVA0.97870.9511515
TYK2-KEAP1chr1910476192chr19106029381011HLA-B41:01VEEEVNKEEVA0.99850.9446415
TYK2-KEAP1chr1910476192chr19106029381011HLA-B44:07EEVAKQEEF0.99910.95581120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B44:13EEVAKQEEF0.99910.95581120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B44:26EEVAKQEEF0.99910.95581120
TYK2-KEAP1chr1910476192chr19106029381011HLA-A25:01EVAKQEEFF0.99850.85051221
TYK2-KEAP1chr1910476192chr19106029381011HLA-B18:04EEVAKQEEF0.99670.84921120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B18:11EEVAKQEEF0.99650.72441120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B18:08EEVAKQEEF0.99640.82261120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B18:07EEVAKQEEF0.99630.80451120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B18:05EEVAKQEEF0.99590.83071120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B18:06EEVAKQEEF0.9950.8391120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B18:03EEVAKQEEF0.99170.82351120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B40:04EEVAKQEEF0.97870.66161120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B35:20EEVAKQEEF0.78030.82331120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B41:03EEVAKQEEF0.68650.51891120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B15:53EEVAKQEEF0.45190.78761120
TYK2-KEAP1chr1910476192chr19106029381011HLA-B44:13EEVAKQEEFF0.99750.96161121
TYK2-KEAP1chr1910476192chr19106029381011HLA-B44:07EEVAKQEEFF0.99750.96161121
TYK2-KEAP1chr1910476192chr19106029381011HLA-B44:26EEVAKQEEFF0.99750.96161121
TYK2-KEAP1chr1910476192chr19106029381011HLA-B44:13KEEVAKQEEF0.99550.96711020
TYK2-KEAP1chr1910476192chr19106029381011HLA-B44:26KEEVAKQEEF0.99550.96711020
TYK2-KEAP1chr1910476192chr19106029381011HLA-B44:07KEEVAKQEEF0.99550.96711020
TYK2-KEAP1chr1910476192chr19106029381011HLA-B41:03KEEVAKQEEF0.86480.55031020

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Potential FusionNeoAntigen Information of TYK2-KEAP1 in HLA II

check button Multiple sequence alignments of the potential FusionNeoAntigens per fusion breakpoints. If the MSA is empty, then it means that there were predicted fusion neoantigens in this fusion breakpoint, but those predicted fusion neoantigens were not across the breakpoint, which is not fusion-specific.

check button Potential FusionNeoAntigen Information
* We used NetMHCIIpan v4.1 (%rank<0.5).
Fusion geneHchrHbpTgeneTchrTbpHLA IIFusionNeoAntigen peptideNeoantigen start (at BP 13)Neoantigen end (at BP 13)

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Fusion breakpoint peptide structures of TYK2-KEAP1

check button3D structures of the fusion breakpoint peptide of 14AA sequence that have potential fusion neoantigens
* The minimum length of the amino acid sequence in RoseTTAFold is 14AA. Here, we predicted the 14AA fusion protein breakpoint sequence not the fusion neoantigen peptide, which is shorter than 14 AA.
File nameBPseqHgeneTgeneHchrHbpTchrTbpAAlen
1706EEVNKEEVAKQEEFTYK2KEAP1chr1910476192chr19106029381011

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D of TYK2-KEAP1

check buttonVirtual screening between 25 HLAs (from PDB) and FusionNeoAntigens
* We used Glide to predict the interaction between HLAs and neoantigens.
HLA allelePDB IDFile nameBPseqDocking scoreGlide score
HLA-B14:023BVN1706EEVNKEEVAKQEEF-7.4838-7.5956
HLA-B14:023BVN1706EEVNKEEVAKQEEF-3.16066-4.20376
HLA-B52:013W391706EEVNKEEVAKQEEF-6.93679-7.04859
HLA-B52:013W391706EEVNKEEVAKQEEF-6.10064-7.14374
HLA-A11:014UQ21706EEVNKEEVAKQEEF-7.21307-7.32487
HLA-A24:025HGA1706EEVNKEEVAKQEEF-6.56769-6.67949
HLA-A24:025HGA1706EEVNKEEVAKQEEF-4.65311-5.69621
HLA-B44:053DX81706EEVNKEEVAKQEEF-6.68002-6.79182
HLA-B44:053DX81706EEVNKEEVAKQEEF-3.22493-4.26803

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Vaccine Design for the FusionNeoAntigens of TYK2-KEAP1

check button mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-Is.
Fusion geneHchrHbpTchrTbpStart in +/-13AAEnd in +/-13AAFusionNeoAntigen peptide sequenceFusionNeoAntigen RNA sequence
TYK2-KEAP1chr1910476192chr19106029381020KEEVAKQEEFAAGGAGGAGGTGGCCAAGCAAGAGGAGTTC
TYK2-KEAP1chr1910476192chr19106029381120EEVAKQEEFGAGGAGGTGGCCAAGCAAGAGGAGTTC
TYK2-KEAP1chr1910476192chr19106029381121EEVAKQEEFFGAGGAGGTGGCCAAGCAAGAGGAGTTCTTC
TYK2-KEAP1chr1910476192chr19106029381221EVAKQEEFFGAGGTGGCCAAGCAAGAGGAGTTCTTC
TYK2-KEAP1chr1910476192chr1910602938415VEEEVNKEEVAGTAGAGGAGGAGGTGAACAAGGAGGAGGTGGCC
TYK2-KEAP1chr1910476192chr1910602938514EEEVNKEEVGAGGAGGAGGTGAACAAGGAGGAGGTG
TYK2-KEAP1chr1910476192chr1910602938515EEEVNKEEVAGAGGAGGAGGTGAACAAGGAGGAGGTGGCC
TYK2-KEAP1chr1910476192chr1910602938615EEVNKEEVAGAGGAGGTGAACAAGGAGGAGGTGGCC

check button mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-IIs.
Fusion geneHchrHbpTchrTbpStart in +/-13AAEnd in +/-13AAFusionNeoAntigen peptideFusionNEoAntigen RNA sequence

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Information of the samples that have these potential fusion neoantigens of TYK2-KEAP1

check button These samples were reported as having these fusion breakpoints. For individual breakpoints, we checked the open reading frames considering multiple gene isoforms and chose the in-frame fusion genes only. Then, we made fusion protein sequences and predicted the fusion neoantigens. These fusion-positive samples may have these potential fusion neoantigens.
Cancer typeFusion geneHchrHbpHenstTchrTbpTenstSample
LUSCTYK2-KEAP1chr1910476192ENST00000264818chr1910602938ENST00000171111TCGA-77-A5GH

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Potential target of CAR-T therapy development for TYK2-KEAP1

check button Predicted 3D structure. We used RoseTTAFold.

check buttonRetention analysis result of each fusion partner 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, to provide the retention of the transmembrane domain, we only show the protein feature retention information of those transmembrane features


* Minus value of BPloci means that the break point is located before the CDS.
- In-frame and retained 'Transmembrane'.
PartnerGeneHbpTbpENSTStrandBPexonTotalExonProtein feature loci*BPlociTotalLenProtein featureProtein feature note

check button Subcellular localization prediction of the transmembrane domain retained fusion proteins
* We used DeepLoc 1.0. The order of the X-axis of the barplot is as follows: Entry_ID, Localization, Type, Nucleus, Cytoplasm, Extracellular, Mitochondrion, Cell_membrane, Endoplasmic_reticulum, Plastid, Golgi.apparatus, Lysosome.Vacuole, Peroxisome. Y-axis is the output score of DeepLoc. Clicking the image will open a new tab with a large image.
HgeneHchrHbpHenstTgeneTchrTbpTenstDeepLoc result

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Related Drugs to TYK2-KEAP1

check button Drugs used for this fusion-positive patient.
(Manual curation of PubMed, 04-30-2022 + MyCancerGenome)
HgeneTgeneDrugSourcePMID

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Related Diseases to TYK2-KEAP1

check button Diseases that have this fusion gene.
(Manual curation of PubMed, 04-30-2022 + MyCancerGenome)
HgeneTgeneDiseaseSourcePMID

check button Diseases associated with fusion partners.
(DisGeNet 4.0)
PartnerGeneDisease IDDisease name# pubmedsSource