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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:APPL2-NR0B1

Fusion Gene and Fusion Protein Summary

check button Fusion gene summary
Fusion partner gene informationFusion gene name: APPL2-NR0B1
FusionPDB ID: 5690
FusionGDB2.0 ID: 5690
HgeneTgene
Gene symbol

APPL2

NR0B1

Gene ID

55198

190

Gene nameadaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2nuclear receptor subfamily 0 group B member 1
SynonymsDIP13BAHC|AHCH|AHX|DAX-1|DAX1|DSS|GTD|HHG|NROB1|SRXY2
Cytomap

12q23.3

Xp21.2

Type of geneprotein-codingprotein-coding
DescriptionDCC-interacting protein 13-betaDIP13 betaadapter protein containing PH domain, PTB domain and leucine zipper motif 2adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 2nuclear receptor subfamily 0 group B member 1DSS-AHC critical region on the X chromosome protein 1nuclear hormone receptornuclear receptor DAX-1truncated nuclear receptor subfamily 0 group B member 1
Modification date2020031320200313
UniProtAcc

Q8NEU8

Main function of 5'-partner protein: FUNCTION: Multifunctional adapter protein that binds to various membrane receptors, nuclear factors and signaling proteins to regulate many processes, such as cell proliferation, immune response, endosomal trafficking and cell metabolism (PubMed:26583432, PubMed:15016378, PubMed:24879834). Regulates signaling pathway leading to cell proliferation through interaction with RAB5A and subunits of the NuRD/MeCP1 complex (PubMed:15016378). Plays a role in immune response by modulating phagocytosis, inflammatory and innate immune responses. In macrophages, enhances Fc-gamma receptor-mediated phagocytosis through interaction with RAB31 leading to activation of PI3K/Akt signaling. In response to LPS, modulates inflammatory responses by playing a key role on the regulation of TLR4 signaling and in the nuclear translocation of RELA/NF-kappa-B p65 and the secretion of pro- and anti-inflammatory cytokines. Also functions as a negative regulator of innate immune response via inhibition of AKT1 signaling pathway by forming a complex with APPL1 and PIK3R1 (By similarity). Plays a role in endosomal trafficking of TGFBR1 from the endosomes to the nucleus (PubMed:26583432). Plays a role in cell metabolism by regulating adiponecting ans insulin signaling pathways and adaptative thermogenesis (PubMed:24879834) (By similarity). In muscle, negatively regulates adiponectin-simulated glucose uptake and fatty acid oxidation by inhibiting adiponectin signaling pathway through APPL1 sequestration thereby antagonizing APPL1 action (By similarity). In muscles, negativeliy regulates insulin-induced plasma membrane recruitment of GLUT4 and glucose uptake through interaction with TBC1D1 (PubMed:24879834). Plays a role in cold and diet-induced adaptive thermogenesis by activating ventromedial hypothalamus (VMH) neurons throught AMPK inhibition which enhances sympathetic outflow to subcutaneous white adipose tissue (sWAT), sWAT beiging and cold tolerance (By similarity). Also plays a role in other signaling pathways namely Wnt/beta-catenin, HGF and glucocorticoid receptor signaling (PubMed:19433865) (By similarity). Positive regulator of beta-catenin/TCF-dependent transcription through direct interaction with RUVBL2/reptin resulting in the relief of RUVBL2-mediated repression of beta-catenin/TCF target genes by modulating the interactions within the beta-catenin-reptin-HDAC complex (PubMed:19433865). May affect adult neurogenesis in hippocampus and olfactory system via regulating the sensitivity of glucocorticoid receptor. Required for fibroblast migration through HGF cell signaling (By similarity). {ECO:0000250|UniProtKB:Q8K3G9, ECO:0000269|PubMed:15016378, ECO:0000269|PubMed:19433865, ECO:0000269|PubMed:24879834, ECO:0000269|PubMed:26583432}.
.
Ensembl transtripts involved in fusion geneENST idsENST00000258530, ENST00000539978, 
ENST00000551662, ENST00000549573, 
ENST00000546731, 
ENST00000378963, 
ENST00000453287, ENST00000378970, 
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)* DoF score9 X 10 X 5=4502 X 1 X 2=4
# samples 103
** MAII scorelog2(10/450*10)=-2.16992500144231
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
log2(3/4*10)=2.90689059560852
Fusion gene context

PubMed: APPL2 [Title/Abstract] AND NR0B1 [Title/Abstract] AND fusion [Title/Abstract]

Fusion neoantigen context

PubMed: APPL2 [Title/Abstract] AND NR0B1 [Title/Abstract] AND neoantigen [Title/Abstract]

Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)APPL2(105597481)-NR0B1(30322940), # samples:1
Anticipated loss of major functional domain due to fusion event.APPL2-NR0B1 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.
APPL2-NR0B1 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.
APPL2-NR0B1 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.
APPL2-NR0B1 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
HgeneAPPL2

GO:0006606

protein import into nucleus

26583432

HgeneAPPL2

GO:0051289

protein homotetramerization

23055524

HgeneAPPL2

GO:2000045

regulation of G1/S transition of mitotic cell cycle

15016378

TgeneNR0B1

GO:0006694

steroid biosynthetic process

9384387

TgeneNR0B1

GO:0008104

protein localization

11875111

TgeneNR0B1

GO:0033144

negative regulation of intracellular steroid hormone receptor signaling pathway

11875111

TgeneNR0B1

GO:0045892

negative regulation of transcription, DNA-templated

7990953|9384387



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/chr12:105597481/chrX:30322940)
- 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 APPL2 (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 NR0B1 (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)
ENST00000258530APPL2chr12105597481-ENST00000378970NR0B1chrX30322940-154893079999306
ENST00000539978APPL2chr12105597481-ENST00000378970NR0B1chrX30322940-162810102191079286
ENST00000551662APPL2chr12105597481-ENST00000378970NR0B1chrX30322940-141179323862279

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
ENST00000258530ENST00000378970APPL2chr12105597481-NR0B1chrX30322940-0.0004817710.9995183
ENST00000539978ENST00000378970APPL2chr12105597481-NR0B1chrX30322940-0.001172030.998828
ENST00000551662ENST00000378970APPL2chr12105597481-NR0B1chrX30322940-0.0007477380.99925226

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 APPL2-NR0B1

check button +/-13 AA sequence from the breakpoints of the fusion protein sequences.
HgeneHchrHbpTgeneTchrTbpLength(fusion protein)BP in fusion proteinPeptide
APPL2chr12105597481NR0B1chrX303229401010263MDSFLSSVADMVQRRAGPAVREVHSG
APPL2chr12105597481NR0B1chrX30322940793256MDSFLSSVADMVQRRAGPAVREVHSG
APPL2chr12105597481NR0B1chrX30322940930283MDSFLSSVADMVQRRAGPAVREVHSG

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Potential FusionNeoAntigen Information of APPL2-NR0B1 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.
APPL2-NR0B1_105597481_30322940.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)
APPL2-NR0B1chr12105597481chrX30322940930HLA-A68:24SVADMVQRR0.99820.6186615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A68:03SVADMVQRR0.99680.594615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A66:01SVADMVQRR0.9940.5635615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A68:05SVADMVQRR0.99190.6074615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A31:06SVADMVQRR0.98860.5247615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A74:09SVADMVQRR0.95710.7251615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A74:03SVADMVQRR0.95710.7251615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A74:11SVADMVQRR0.95710.7251615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A31:02SVADMVQRR0.92870.6659615
APPL2-NR0B1chr12105597481chrX30322940930HLA-B48:01VQRRAGPAV0.91840.64751120
APPL2-NR0B1chr12105597481chrX30322940930HLA-A34:01SVADMVQRR0.91550.5741615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A34:05SVADMVQRR0.91550.5741615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A26:03SVADMVQRR0.91510.5781615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A66:03SVADMVQRR0.91270.5319615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A74:11SSVADMVQR0.88960.5506514
APPL2-NR0B1chr12105597481chrX30322940930HLA-A74:09SSVADMVQR0.88960.5506514
APPL2-NR0B1chr12105597481chrX30322940930HLA-A74:03SSVADMVQR0.88960.5506514
APPL2-NR0B1chr12105597481chrX30322940930HLA-A31:02SSVADMVQR0.85210.5301514
APPL2-NR0B1chr12105597481chrX30322940930HLA-B07:10VQRRAGPAV0.53810.68991120
APPL2-NR0B1chr12105597481chrX30322940930HLA-B13:02VQRRAGPAV0.49180.87641120
APPL2-NR0B1chr12105597481chrX30322940930HLA-B52:01VQRRAGPAV0.0190.96241120
APPL2-NR0B1chr12105597481chrX30322940930HLA-A66:01SSVADMVQRR0.97910.5063515
APPL2-NR0B1chr12105597481chrX30322940930HLA-A68:01SVADMVQRR0.99820.6186615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A31:01SVADMVQRR0.95970.6314615
APPL2-NR0B1chr12105597481chrX30322940930HLA-B15:04VQRRAGPAV0.83380.8591120
APPL2-NR0B1chr12105597481chrX30322940930HLA-B27:10QRRAGPAVR0.98690.7371221
APPL2-NR0B1chr12105597481chrX30322940930HLA-A74:01SVADMVQRR0.95710.7251615
APPL2-NR0B1chr12105597481chrX30322940930HLA-A66:02SVADMVQRR0.94120.5283615
APPL2-NR0B1chr12105597481chrX30322940930HLA-B15:73VQRRAGPAV0.90880.92181120
APPL2-NR0B1chr12105597481chrX30322940930HLA-A74:01SSVADMVQR0.88960.5506514
APPL2-NR0B1chr12105597481chrX30322940930HLA-B15:30VQRRAGPAV0.82660.88091120
APPL2-NR0B1chr12105597481chrX30322940930HLA-B15:68VQRRAGPAV0.71910.66511120

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Potential FusionNeoAntigen Information of APPL2-NR0B1 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.
APPL2-NR0B1_105597481_30322940.msa

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)
APPL2-NR0B1chr12105597481chrX30322940930DRB1-0704MDSFLSSVADMVQRR015
APPL2-NR0B1chr12105597481chrX30322940930DRB1-0904MDSFLSSVADMVQRR015
APPL2-NR0B1chr12105597481chrX30322940930DRB1-0905MDSFLSSVADMVQRR015
APPL2-NR0B1chr12105597481chrX30322940930DRB1-0907MDSFLSSVADMVQRR015

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Fusion breakpoint peptide structures of APPL2-NR0B1

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
9137SVADMVQRRAGPAVAPPL2NR0B1chr12105597481chrX30322940930

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D of APPL2-NR0B1

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-B14:023BVN9137SVADMVQRRAGPAV-5.97758-6.09098
HLA-B14:023BVN9137SVADMVQRRAGPAV-5.15013-6.18543
HLA-B52:013W399137SVADMVQRRAGPAV-6.29935-6.41275
HLA-B52:013W399137SVADMVQRRAGPAV-6.07479-7.11009
HLA-A24:025HGA9137SVADMVQRRAGPAV-7.25246-8.28776
HLA-A24:025HGA9137SVADMVQRRAGPAV-6.23064-6.34404
HLA-B44:053DX89137SVADMVQRRAGPAV-4.66421-5.69951
HLA-B44:053DX89137SVADMVQRRAGPAV-4.52141-4.63481
HLA-A02:016TDR9137SVADMVQRRAGPAV-7.72945-7.84285

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Vaccine Design for the FusionNeoAntigens of APPL2-NR0B1

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
APPL2-NR0B1chr12105597481chrX303229401120VQRRAGPAVTCAAAGACGTGCCGGGCCTGCAGTGCG
APPL2-NR0B1chr12105597481chrX303229401221QRRAGPAVRAAGACGTGCCGGGCCTGCAGTGCGTGA
APPL2-NR0B1chr12105597481chrX30322940514SSVADMVQRCTCCGTTGCAGACATGGTTCAAAGACG
APPL2-NR0B1chr12105597481chrX30322940515SSVADMVQRRCTCCGTTGCAGACATGGTTCAAAGACGTGC
APPL2-NR0B1chr12105597481chrX30322940615SVADMVQRRCGTTGCAGACATGGTTCAAAGACGTGC

check button mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-IIs.
Fusion geneHchrHbpTchrTbpStart in +/-13AAEnd in +/-13AAFusionNeoAntigen peptideFusionNEoAntigen RNA sequence
APPL2-NR0B1chr12105597481chrX30322940015MDSFLSSVADMVQRRGGACAGCTTTTTATCCTCCGTTGCAGACATGGTTCAAAGACGTGC

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Information of the samples that have these potential fusion neoantigens of APPL2-NR0B1

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
UCECAPPL2-NR0B1chr12105597481ENST00000258530chrX30322940ENST00000378970TCGA-AJ-A3BD-01A

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Potential target of CAR-T therapy development for APPL2-NR0B1

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 APPL2-NR0B1

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 APPL2-NR0B1

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