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Fusion Protein:ORC4-MAPK4

Fusion Gene and Fusion Protein Summary

Fusion gene summary

Fusion partner gene information	Fusion gene name: ORC4-MAPK4
	FusionPDB ID: 61681
	FusionGDB2.0 ID: 61681
		Hgene	Tgene
	Gene symbol	ORC4	MAPK4
	Gene ID	5000	5596
	Gene name	origin recognition complex subunit 4	mitogen-activated protein kinase 4
	Synonyms	ORC4L\|ORC4P	ERK-4\|ERK4\|PRKM4\|p63-MAPK\|p63MAPK
	Cytomap	2q23.1	18q21.1-q21.2
	Type of gene	protein-coding	protein-coding
	Description	origin recognition complex subunit 4origin recognition complex, subunit 4 homolog	mitogen-activated protein kinase 4Erk3-relatedMAP kinase isoform p63MAPK 4extracellular signal-regulated kinase 4
	Modification date	20200313	20200313
	UniProtAcc	.	P31152 Main function of 5'-partner protein: FUNCTION: Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK4/MAPK4 is phosphorylated at Ser-186 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK4/MAPK4. May promote entry in the cell cycle (By similarity). {ECO:0000250}.
Ensembl transtripts involved in fusion gene	ENST ids	ENST00000264169, ENST00000392857, ENST00000392858, ENST00000535373, ENST00000536575, ENST00000540442, ENST00000542387, ENST00000488761,	ENST00000587823, ENST00000588540, ENST00000400384, ENST00000540640, ENST00000592595,
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)	* DoF score	7 X 8 X 4=224	3 X 3 X 3=27
	# samples	8	3
	** MAII score	log2(8/224*10)=-1.48542682717024 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0	log2(3/27*10)=0.15200309344505 effective Gene in Pan-Cancer Fusion Genes (eGinPCFGs). DoF>8 and MAII>0
Fusion gene context	PubMed: ORC4 [Title/Abstract] AND MAPK4 [Title/Abstract] AND fusion [Title/Abstract]
Fusion neoantigen context	PubMed: ORC4 [Title/Abstract] AND MAPK4 [Title/Abstract] AND neoantigen [Title/Abstract]
Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)	ORC4(148709942)-MAPK4(48255528), # samples:3
Anticipated loss of major functional domain due to fusion event.	ORC4-MAPK4 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. ORC4-MAPK4 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. ORC4-MAPK4 seems lost the major protein functional domain in Hgene partner, which is a essential gene due to the frame-shifted ORF. ORC4-MAPK4 seems lost the major protein functional domain in Tgene partner, which is a essential gene due to the frame-shifted ORF. ORC4-MAPK4 seems lost the major protein functional domain in Tgene partner, which is a IUPHAR drug target due to the frame-shifted ORF. ORC4-MAPK4 seems lost the major protein functional domain in Tgene partner, which is a kinase 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)

Gene ontology of each fusion partner gene with evidence of Inferred from Direct Assay (IDA) from Entrez

Partner

Gene

GO ID

GO term

PubMed ID

Four levels of functional features of fusion genes
Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr2:148709942/chr18:48255528)
- 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.

Retention 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.

Fusion gene breakpoints across ORC4 (5'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

Fusion gene breakpoints across MAPK4 (3'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

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Fusion Amino Acid Sequences

Fusion information from ORFfinder translation from full-length transcript sequence from FusionPDB.

Henst	Tenst	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand	Seq length (transcript)	BP loci (transcript)	Predicted start (transcript)	Predicted stop (transcript)	Seq length (amino acids)
ENST00000392857	ORC4	chr2	148709942	-	ENST00000400384	MAPK4	chr18	48255528	+	3363	696	676	1392	238
ENST00000392858	ORC4	chr2	148709942	-	ENST00000540640	MAPK4	chr18	48255528	+	1692	748	728	1444	238
ENST00000392858	ORC4	chr2	148709942	-	ENST00000592595	MAPK4	chr18	48255528	+	3415	748	728	1444	238
ENST00000535373	ORC4	chr2	148709942	-	ENST00000540640	MAPK4	chr18	48255528	+	1965	1021	1001	1717	238
ENST00000535373	ORC4	chr2	148709942	-	ENST00000592595	MAPK4	chr18	48255528	+	3688	1021	1001	1717	238
ENST00000536575	ORC4	chr2	148709942	-	ENST00000400384	MAPK4	chr18	48255528	+	3292	625	605	1321	238
ENST00000540442	ORC4	chr2	148709942	-	ENST00000400384	MAPK4	chr18	48255528	+	3460	793	773	1489	238
ENST00000264169	ORC4	chr2	148709942	-	ENST00000540640	MAPK4	chr18	48255528	+	1680	736	716	1432	238
ENST00000264169	ORC4	chr2	148709942	-	ENST00000592595	MAPK4	chr18	48255528	+	3403	736	716	1432	238
ENST00000392857	ORC4	chr2	148712916	-	ENST00000540640	MAPK4	chr18	48255528	+	1488	544	557	1240	227
ENST00000392857	ORC4	chr2	148712916	-	ENST00000592595	MAPK4	chr18	48255528	+	3211	544	557	1240	227
ENST00000536575	ORC4	chr2	148712916	-	ENST00000540640	MAPK4	chr18	48255528	+	1417	473	486	1169	227
ENST00000536575	ORC4	chr2	148712916	-	ENST00000592595	MAPK4	chr18	48255528	+	3140	473	486	1169	227
ENST00000540442	ORC4	chr2	148712916	-	ENST00000540640	MAPK4	chr18	48255528	+	1585	641	654	1337	227
ENST00000540442	ORC4	chr2	148712916	-	ENST00000592595	MAPK4	chr18	48255528	+	3308	641	654	1337	227

DeepORF 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.

Henst	Tenst	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand	No-coding score	Coding score
ENST00000392857	ENST00000400384	ORC4	chr2	148709942	-	MAPK4	chr18	48255528	+	0.007591892	0.99240804
ENST00000392858	ENST00000540640	ORC4	chr2	148709942	-	MAPK4	chr18	48255528	+	0.010735203	0.9892647
ENST00000392858	ENST00000592595	ORC4	chr2	148709942	-	MAPK4	chr18	48255528	+	0.007252471	0.9927475
ENST00000535373	ENST00000540640	ORC4	chr2	148709942	-	MAPK4	chr18	48255528	+	0.020723136	0.97927684
ENST00000535373	ENST00000592595	ORC4	chr2	148709942	-	MAPK4	chr18	48255528	+	0.007948621	0.99205136
ENST00000536575	ENST00000400384	ORC4	chr2	148709942	-	MAPK4	chr18	48255528	+	0.01992342	0.9800766
ENST00000540442	ENST00000400384	ORC4	chr2	148709942	-	MAPK4	chr18	48255528	+	0.020261424	0.9797386
ENST00000264169	ENST00000540640	ORC4	chr2	148709942	-	MAPK4	chr18	48255528	+	0.010913321	0.9890866
ENST00000264169	ENST00000592595	ORC4	chr2	148709942	-	MAPK4	chr18	48255528	+	0.008585583	0.99141437
ENST00000392857	ENST00000540640	ORC4	chr2	148712916	-	MAPK4	chr18	48255528	+	0.050576527	0.94942343
ENST00000392857	ENST00000592595	ORC4	chr2	148712916	-	MAPK4	chr18	48255528	+	0.020201344	0.9797987
ENST00000536575	ENST00000540640	ORC4	chr2	148712916	-	MAPK4	chr18	48255528	+	0.03756429	0.9624357
ENST00000536575	ENST00000592595	ORC4	chr2	148712916	-	MAPK4	chr18	48255528	+	0.013784529	0.9862155
ENST00000540442	ENST00000540640	ORC4	chr2	148712916	-	MAPK4	chr18	48255528	+	0.04594392	0.9540561
ENST00000540442	ENST00000592595	ORC4	chr2	148712916	-	MAPK4	chr18	48255528	+	0.019169005	0.98083097

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 ORC4-MAPK4

+/-13 AA sequence from the breakpoints of the fusion protein sequences.

Hgene

Hchr

Hbp

Tgene

Tchr

Tbp

Length(fusion protein)

BP in fusion protein

Peptide

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Potential FusionNeoAntigen Information of ORC4-MAPK4 in HLA I

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.

Potential FusionNeoAntigen Information
* We used NetMHCpan v4.1 (%rank<0.5) and deepHLApan v1.1 (immunogenic score>0.5)

Fusion gene

Hchr

Hbp

Tgene

Tchr

Tbp

HLA I

FusionNeoAntigen peptide

Binding score

Immunogenic score

Neoantigen start (at BP 13)

Neoantigen end (at BP 13)

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Potential FusionNeoAntigen Information of ORC4-MAPK4 in HLA II

Potential FusionNeoAntigen Information
* We used NetMHCIIpan v4.1 (%rank<0.5).

Fusion gene

Hchr

Hbp

Tgene

Tchr

Tbp

HLA II

FusionNeoAntigen peptide

Neoantigen start (at BP 13)

Neoantigen end (at BP 13)

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Fusion breakpoint peptide structures of ORC4-MAPK4

3D 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 ORC4-MAPK4

Virtual screening between 25 HLAs (from PDB) and FusionNeoAntigens
* We used Glide to predict the interaction between HLAs and neoantigens.

HLA allele

PDB ID

File name

BPseq

Docking score

Glide score

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Vaccine Design for the FusionNeoAntigens of ORC4-MAPK4

mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-Is.

Fusion gene

Hchr

Hbp

Tchr

Tbp

Start in +/-13AA

End in +/-13AA

FusionNeoAntigen peptide sequence

FusionNeoAntigen RNA sequence

mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-IIs.

Fusion gene

Hchr

Hbp

Tchr

Tbp

Start in +/-13AA

End in +/-13AA

FusionNeoAntigen peptide

FusionNEoAntigen RNA sequence

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Information of the samples that have these potential fusion neoantigens of ORC4-MAPK4

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 type

Fusion gene

Hchr

Hbp

Henst

Tchr

Tbp

Tenst

Sample

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Potential target of CAR-T therapy development for ORC4-MAPK4

Predicted 3D structure. We used RoseTTAFold.

Retention 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'.

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Protein feature

Protein feature note

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.

Hgene

Hchr

Hbp

Henst

Tgene

Tchr

Tbp

Tenst

DeepLoc result

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Related Drugs to ORC4-MAPK4

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

Hgene

Tgene

Drug

Source

PMID

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Related Diseases to ORC4-MAPK4

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

Hgene

Tgene

Disease

Source

PMID

Diseases associated with fusion partners.
(DisGeNet 4.0)

Partner

Gene

Disease ID

Disease name

# pubmeds

Source

	Fusion Gene and Fusion Protein Summary
	Fusion Amino Acid Sequences (multiple BPs and multiple gene isoforms)
	Fusion Protein Breakpoint Sequences - (for the Screening of the FusionNeoAntigens)
	Potential FusionNeoAntigens in HLA I - (netMHCpan v4.1 + deepHLApan v1.1)
	Potential FusionNeoAntigens in HLA II - (netMHCIIpan v4.1)
	Fusion Breakpoint 14 AA Peptide Structure - (RoseTTAFold)
	Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D - (Glide)
	Vaccine Design for the FusionNeoAntigens (RNA/protein sequences)
	Potential target of CAR-T therapy development
	Information on the samples that have these potential fusion neoantigens
	Fusion Protein Targeting Drugs - (Manual Curation)
	Fusion Protein Related diseases - (Manual Curation)