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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:CUL3-AP1S3

Fusion Gene and Fusion Protein Summary

check button Fusion gene summary
Fusion partner gene informationFusion gene name: CUL3-AP1S3
FusionPDB ID: 20663
FusionGDB2.0 ID: 20663
HgeneTgene
Gene symbol

CUL3

AP1S3

Gene ID

8452

130340

Gene namecullin 3adaptor related protein complex 1 subunit sigma 3
SynonymsCUL-3|PHA2EPSORS15
Cytomap

2q36.2

2q36.1

Type of geneprotein-codingprotein-coding
Descriptioncullin-3AP-1 complex subunit sigma-3adapter-related protein complex 1 subunit sigma-1Cadaptor protein complex AP-1 sigma-1C subunitadaptor related protein complex 1 sigma 3 subunitadaptor-related protein complex 1 subunit sigma-1Cclathrin assembly protein co
Modification date2020032720200313
UniProtAcc

Q13618

Main function of 5'-partner protein: FUNCTION: Core component of multiple cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. BCR complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the BCR complex depends on the BTB domain-containing protein as the substrate recognition component. BCR(KLHL42) is involved in ubiquitination of KATNA1. BCR(SPOP) is involved in ubiquitination of BMI1/PCGF4, BRMS1, MACROH2A1 and DAXX, GLI2 and GLI3. Can also form a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL; these complexes have lower ubiquitin ligase activity. BCR(KLHL9-KLHL13) controls the dynamic behavior of AURKB on mitotic chromosomes and thereby coordinates faithful mitotic progression and completion of cytokinesis. BCR(KLHL12) is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) acts by mediating monoubiquitination of SEC31 (SEC31A or SEC31B) (PubMed:22358839, PubMed:27716508). BCR(KLHL3) acts as a regulator of ion transport in the distal nephron; by mediating ubiquitination of WNK4 (PubMed:23387299, PubMed:23453970, PubMed:23576762). The BCR(KLHL20) E3 ubiquitin ligase complex is involved in interferon response and anterograde Golgi to endosome transport: it mediates both ubiquitination leading to degradation and 'Lys-33'-linked ubiquitination (PubMed:20389280, PubMed:21840486, PubMed:21670212, PubMed:24768539). The BCR(KLHL21) E3 ubiquitin ligase complex regulates localization of the chromosomal passenger complex (CPC) from chromosomes to the spindle midzone in anaphase and mediates the ubiquitination of AURKB (PubMed:19995937). The BCR(KLHL22) ubiquitin ligase complex mediates monoubiquitination of PLK1, leading to PLK1 dissociation from phosphoreceptor proteins and subsequent removal from kinetochores, allowing silencing of the spindle assembly checkpoint (SAC) and chromosome segregation (PubMed:23455478). The BCR(KLHL22) ubiquitin ligase complex is also responsible for the amino acid-stimulated 'Lys-48' polyubiquitination and proteasomal degradation of DEPDC5. Through the degradation of DEPDC5, releases the GATOR1 complex-mediated inhibition of the TORC1 pathway (PubMed:29769719). The BCR(KLHL25) ubiquitin ligase complex is involved in translational homeostasis by mediating ubiquitination and subsequent degradation of hypophosphorylated EIF4EBP1 (4E-BP1) (PubMed:22578813). The BCR(KBTBD8) complex acts by mediating monoubiquitination of NOLC1 and TCOF1, leading to remodel the translational program of differentiating cells in favor of neural crest specification (PubMed:26399832). Involved in ubiquitination of cyclin E and of cyclin D1 (in vitro) thus involved in regulation of G1/S transition. Involved in the ubiquitination of KEAP1, ENC1 and KLHL41 (PubMed:15983046). In concert with ATF2 and RBX1, promotes degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. The BCR(KCTD17) E3 ubiquitin ligase complex mediates ubiquitination and degradation of TCHP, a down-regulator of cilium assembly, thereby inducing ciliogenesis (PubMed:25270598). The BCR(KLHL24) E3 ubiquitin ligase complex mediates ubiquitination of KRT14, controls KRT14 levels during keratinocytes differentiation, and is essential for skin integrity (PubMed:27798626). The BCR(KLHL18) E3 ubiquitin ligase complex mediates the ubiquitination of AURKA leading to its activation at the centrosome which is required for initiating mitotic entry (PubMed:23213400). The BCR(KEAP1) E3 ubiquitin ligase complex acts as a key sensor of oxidative and electrophilic stress by mediating ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes (PubMed:15601839, PubMed:16006525). {ECO:0000269|PubMed:10500095, ECO:0000269|PubMed:11311237, ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:15897469, ECO:0000269|PubMed:15983046, ECO:0000269|PubMed:16006525, ECO:0000269|PubMed:16524876, ECO:0000269|PubMed:17543862, ECO:0000269|PubMed:18397884, ECO:0000269|PubMed:19261606, ECO:0000269|PubMed:19995937, ECO:0000269|PubMed:20389280, ECO:0000269|PubMed:21670212, ECO:0000269|PubMed:21840486, ECO:0000269|PubMed:22085717, ECO:0000269|PubMed:22358839, ECO:0000269|PubMed:22578813, ECO:0000269|PubMed:22632832, ECO:0000269|PubMed:23213400, ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23455478, ECO:0000269|PubMed:23576762, ECO:0000269|PubMed:24768539, ECO:0000269|PubMed:25270598, ECO:0000269|PubMed:26399832, ECO:0000269|PubMed:27565346, ECO:0000269|PubMed:27716508, ECO:0000269|PubMed:27798626, ECO:0000269|PubMed:29769719}.

Q96PC3

Main function of 5'-partner protein: FUNCTION: Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. Involved in TLR3 trafficking (PubMed:24791904). {ECO:0000269|PubMed:24791904}.
Ensembl transtripts involved in fusion geneENST idsENST00000432260, ENST00000409777, 
ENST00000264414, ENST00000344951, 
ENST00000409096, 
ENST00000396653, 
ENST00000396654, ENST00000409375, 
ENST00000423110, ENST00000443700, 
ENST00000446015, 
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)* DoF score12 X 12 X 7=10084 X 2 X 3=24
# samples 145
** MAII scorelog2(14/1008*10)=-2.84799690655495
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
log2(5/24*10)=1.05889368905357
effective Gene in Pan-Cancer Fusion Genes (eGinPCFGs).
DoF>8 and MAII>0
Fusion gene context

PubMed: CUL3 [Title/Abstract] AND AP1S3 [Title/Abstract] AND fusion [Title/Abstract]

Fusion neoantigen context

PubMed: CUL3 [Title/Abstract] AND AP1S3 [Title/Abstract] AND neoantigen [Title/Abstract]

Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)CUL3(225400245)-AP1S3(224642586), # samples:1
Anticipated loss of major functional domain due to fusion event.CUL3-AP1S3 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.
CUL3-AP1S3 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.
CUL3-AP1S3 seems lost the major protein functional domain in Hgene partner, which is a CGC due to the frame-shifted ORF.
CUL3-AP1S3 seems lost the major protein functional domain in Hgene partner, which is a epigenetic factor due to the frame-shifted 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
HgeneCUL3

GO:0000209

protein polyubiquitination

19261606

HgeneCUL3

GO:0006511

ubiquitin-dependent protein catabolic process

25401743|27561354

HgeneCUL3

GO:0006513

protein monoubiquitination

22358839

HgeneCUL3

GO:0006888

ER to Golgi vesicle-mediated transport

22358839

HgeneCUL3

GO:0016567

protein ubiquitination

17543862|19782033|19995937|20389280|23213400

HgeneCUL3

GO:0031145

anaphase-promoting complex-dependent catabolic process

10500095

HgeneCUL3

GO:0043161

proteasome-mediated ubiquitin-dependent protein catabolic process

19261606|19782033|20389280

HgeneCUL3

GO:0071630

nuclear protein quality control by the ubiquitin-proteasome system

27561354



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/chr2:225400245/chr2:224642586)
- 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 CUL3 (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 AP1S3 (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)
ENST00000264414CUL3chr2225400245-ENST00000443700AP1S3chr2224642586-23477173391208289
ENST00000264414CUL3chr2225400245-ENST00000396654AP1S3chr2224642586-14127173391178279
ENST00000264414CUL3chr2225400245-ENST00000396653AP1S3chr2224642586-1171717339905188
ENST00000264414CUL3chr2225400245-ENST00000446015AP1S3chr2224642586-11797173391178279
ENST00000264414CUL3chr2225400245-ENST00000409375AP1S3chr2224642586-11757173391127262
ENST00000264414CUL3chr2225400245-ENST00000423110AP1S3chr2224642586-10297173391028229
ENST00000344951CUL3chr2225400245-ENST00000443700AP1S3chr2224642586-21945643841055223
ENST00000344951CUL3chr2225400245-ENST00000396654AP1S3chr2224642586-12595643841025213
ENST00000344951CUL3chr2225400245-ENST00000396653AP1S3chr2224642586-10185645281176
ENST00000344951CUL3chr2225400245-ENST00000446015AP1S3chr2224642586-10265643841025213
ENST00000344951CUL3chr2225400245-ENST00000409375AP1S3chr2224642586-1022564384974196
ENST00000344951CUL3chr2225400245-ENST00000423110AP1S3chr2224642586-876564384875163
ENST00000409096CUL3chr2225400245-ENST00000443700AP1S3chr2224642586-207944953940295
ENST00000409096CUL3chr2225400245-ENST00000396654AP1S3chr2224642586-114444953910285
ENST00000409096CUL3chr2225400245-ENST00000396653AP1S3chr2224642586-90344953637194
ENST00000409096CUL3chr2225400245-ENST00000446015AP1S3chr2224642586-91144953910286
ENST00000409096CUL3chr2225400245-ENST00000409375AP1S3chr2224642586-90744953859268
ENST00000409096CUL3chr2225400245-ENST00000423110AP1S3chr2224642586-76144953760236

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
ENST00000264414ENST00000443700CUL3chr2225400245-AP1S3chr2224642586-0.0028166990.99718326
ENST00000264414ENST00000396654CUL3chr2225400245-AP1S3chr2224642586-0.0019644110.9980356
ENST00000264414ENST00000396653CUL3chr2225400245-AP1S3chr2224642586-0.0108423960.98915756
ENST00000264414ENST00000446015CUL3chr2225400245-AP1S3chr2224642586-0.0056462710.9943538
ENST00000264414ENST00000409375CUL3chr2225400245-AP1S3chr2224642586-0.0138892410.9861108
ENST00000264414ENST00000423110CUL3chr2225400245-AP1S3chr2224642586-0.0097255550.9902744
ENST00000344951ENST00000443700CUL3chr2225400245-AP1S3chr2224642586-0.0079731090.99202687
ENST00000344951ENST00000396654CUL3chr2225400245-AP1S3chr2224642586-0.0047381810.9952618
ENST00000344951ENST00000396653CUL3chr2225400245-AP1S3chr2224642586-0.183050750.81694925
ENST00000344951ENST00000446015CUL3chr2225400245-AP1S3chr2224642586-0.0110515310.98894846
ENST00000344951ENST00000409375CUL3chr2225400245-AP1S3chr2224642586-0.034767240.96523273
ENST00000344951ENST00000423110CUL3chr2225400245-AP1S3chr2224642586-0.0448890180.95511097
ENST00000409096ENST00000443700CUL3chr2225400245-AP1S3chr2224642586-0.0008870680.9991129
ENST00000409096ENST00000396654CUL3chr2225400245-AP1S3chr2224642586-0.0004911350.99950886
ENST00000409096ENST00000396653CUL3chr2225400245-AP1S3chr2224642586-0.0192503070.98074967
ENST00000409096ENST00000446015CUL3chr2225400245-AP1S3chr2224642586-0.0010840410.99891603
ENST00000409096ENST00000409375CUL3chr2225400245-AP1S3chr2224642586-0.0027435890.99725646
ENST00000409096ENST00000423110CUL3chr2225400245-AP1S3chr2224642586-0.0031055110.9968945

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 CUL3-AP1S3

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

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Potential FusionNeoAntigen Information of CUL3-AP1S3 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.

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)

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Potential FusionNeoAntigen Information of CUL3-AP1S3 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 CUL3-AP1S3

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.

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D of CUL3-AP1S3

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

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Vaccine Design for the FusionNeoAntigens of CUL3-AP1S3

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

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 CUL3-AP1S3

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

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Potential target of CAR-T therapy development for CUL3-AP1S3

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 CUL3-AP1S3

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 CUL3-AP1S3

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