ASpdb: an integrative knowledgebase of human protein isoforms from experimental and AI-predicted structures

Home

Download

Statistics

Examples

Help

Contact

	Protein Summary
	AS Summary
	Protein Functional Features
	Gene Isoform Structures and Expression Levels
	Protein Structures
	pLDDT Score Distribution
	Ramachandran Plot of Protein Structures
	Potential Active Site Information
	Protein Structure and Feature Comparision
	Protein-Protein Interaction
	Related Drugs
	Related Diseases
	Clinically Important Variants

Protein:MDM4

Protein Summary

Gene summary

Gene name: MDM4
ASpdb.0 ID: 4194
	Gene
Gene symbol	MDM4
Gene ID	4194
Gene name	MDM4 regulator of p53
Synonyms	BMFS6\|HDMX\|MDMX\|MRP1
Cytomap	1q32.1
Type of gene	protein-coding
Description	protein Mdm4MDM4, p53 regulatorMDM4-related protein 1Mdm4 p53 binding protein homologdouble minute 4, human homolog of; p53-binding proteinmdm2-like p53-binding proteinprotein Mdmx
Modification date	20240403
UniProtAcc	O15151

Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez

Partner	Gene	GO ID	GO term	PubMed ID
Gene	MDM4	GO:0000122	negative regulation of transcription by RNA polymerase II	9226370
Gene	MDM4	GO:0005654	nucleoplasm	-
Gene	MDM4	GO:0045892	negative regulation of DNA-templated transcription	9271120
Gene	MDM4	GO:0065003	protein-containing complex assembly	10608892

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
O15151-1	O15151-1_3fdo_A.pdb	3FDO	X-ray	1.4	A	23	111

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

O15151

MDM4

O15151-1

O15151-2

490

127

109

490

Substitution

LATATTDAAQTLALAQDHSMDIPSQDQLKQSAEESSTSRKRTTEDDIPTLPTSEHKCIHSREDEDLIENLAQDETSRLDLGFEEWDVAGLPWWFLGNLRSNYTPRSNGSTDLQTNQDVGTAIVSDTTDDLWFLNESVSEQLGVGIKVEAADTEQTSEEVGKVSDKKVIEVGKNDDLEDSKSLSDDTDVEVTSEDEWQCTECKKFNSPSKRYCFRCWALRKDWYSDCSKLTHSLSTSDITAIPEKENEGNDVPDCRRTISAPVVRPKDAYIKKENSKLFDPCNSVEFLDLAHSSESQETISSMGEQLDNLSEQRTDTENMEDCQNLLKPCSLCEKRPRDGNIIHGRTGHLVTCFHCARRLKKAGASCPICKKEIQLVIKVFIA

SASNNTARCNRILQSQKKN

109

127

O15151

MDM4

O15151-1

O15151-3

490

127

109

490

Substitution

SASNNTDAAQTLALAQDHT

109

127

O15151

MDM4

O15151-1

O15151-4

490

164

352

Deletion

none

O15151

MDM4

O15151-1

O15151-5

490

440

225

274

Deletion

none

224

Multiple sequence alignment of our canonical and alternatively spliced MDM4

Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of MDM4

UniProt-id	ENSG	ENST	ENSP
O15151-1	ENSG00000198625.14	ENST00000367182.8	ENSP00000356150.3
O15151-4	ENSG00000198625.14	ENST00000367183.7	ENSP00000356151.3
O15151-5	ENSG00000198625.14	ENST00000454264.6	ENSP00000396840.2

UniProt-id	NM ID	NP ID
O15151-1	NM_002393.4	NP_002384.2
O15151-4	NM_001204172.1	NP_001191101.1
O15151-5	NM_001204171.1	NP_001191100.1

Amino acid sequences of our canonical and alternatively spliced MDM4

accession_id	Protein sequence
O15151-1	MTSFSTSAQCSTSDSACRISPGQINQVRPKLPLLKILHAAGAQGEMFTVKEVMHYLGQYIMVKQLYDQQEQHMVYCGGDLLGELLGRQSF SVKDPSPLYDMLRKNLVTLATATTDAAQTLALAQDHSMDIPSQDQLKQSAEESSTSRKRTTEDDIPTLPTSEHKCIHSREDEDLIENLAQ DETSRLDLGFEEWDVAGLPWWFLGNLRSNYTPRSNGSTDLQTNQDVGTAIVSDTTDDLWFLNESVSEQLGVGIKVEAADTEQTSEEVGKV SDKKVIEVGKNDDLEDSKSLSDDTDVEVTSEDEWQCTECKKFNSPSKRYCFRCWALRKDWYSDCSKLTHSLSTSDITAIPEKENEGNDVP DCRRTISAPVVRPKDAYIKKENSKLFDPCNSVEFLDLAHSSESQETISSMGEQLDNLSEQRTDTENMEDCQNLLKPCSLCEKRPRDGNII
O15151-2	MTSFSTSAQCSTSDSACRISPGQINQVRPKLPLLKILHAAGAQGEMFTVKEVMHYLGQYIMVKQLYDQQEQHMVYCGGDLLGELLGRQSF
O15151-3	MTSFSTSAQCSTSDSACRISPGQINQVRPKLPLLKILHAAGAQGEMFTVKEVMHYLGQYIMVKQLYDQQEQHMVYCGGDLLGELLGRQSF
O15151-4	MTSFSTSAQCSTSDSACRISPGQINQENEGNDVPDCRRTISAPVVRPKDAYIKKENSKLFDPCNSVEFLDLAHSSESQETISSMGEQLDN
O15151-5	MTSFSTSAQCSTSDSACRISPGQINQVRPKLPLLKILHAAGAQGEMFTVKEVMHYLGQYIMVKQLYDQQEQHMVYCGGDLLGELLGRQSF SVKDPSPLYDMLRKNLVTLATATTDAAQTLALAQDHSMDIPSQDQLKQSAEESSTSRKRTTEDDIPTLPTSEHKCIHSREDEDLIENLAQ DETSRLDLGFEEWDVAGLPWWFLGNLRSNYTPRSNGSTDLQTNQVIEVGKNDDLEDSKSLSDDTDVEVTSEDEWQCTECKKFNSPSKRYC FRCWALRKDWYSDCSKLTHSLSTSDITAIPEKENEGNDVPDCRRTISAPVVRPKDAYIKKENSKLFDPCNSVEFLDLAHSSESQETISSM

Protein Functional Features

Main function of this protein. (from UniProt)

MDM4 (go to UniProt):O15151

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
download page
* 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
O15151	Domain	25	108	Note=SWIB/MDM2;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU01273	Type=Deletion;Start=27;End=352
O15151	Zinc finger	300	329	Note=RanBP2-type;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00322	Type=Substitution;Start=109;End=490
O15151	Zinc finger	300	329	Note=RanBP2-type;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00322	Type=Substitution;Start=109;End=490
O15151	Zinc finger	300	329	Note=RanBP2-type;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00322	Type=Deletion;Start=27;End=352
O15151	Zinc finger	437	478	Note=RING-type;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00175	Type=Substitution;Start=109;End=490
O15151	Zinc finger	437	478	Note=RING-type;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00175	Type=Substitution;Start=109;End=490
O15151	Region	129	160	Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=109;End=490
O15151	Region	129	160	Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=109;End=490
O15151	Region	129	160	Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Deletion;Start=27;End=352
O15151	Region	246	332	Note=Region II	Type=Substitution;Start=109;End=490
O15151	Region	246	332	Note=Region II	Type=Substitution;Start=109;End=490
O15151	Region	246	332	Note=Region II	Type=Deletion;Start=27;End=352
O15151	Region	246	332	Note=Region II	Type=Deletion;Start=225;End=274
O15151	Region	393	490	Note=Necessary for interaction with USP2;Ontology_term=ECO:0000269;evidence=ECO:0000269\|PubMed:19838211;Dbxref=PMID:19838211	Type=Substitution;Start=109;End=490
O15151	Region	393	490	Note=Necessary for interaction with USP2;Ontology_term=ECO:0000269;evidence=ECO:0000269\|PubMed:19838211;Dbxref=PMID:19838211	Type=Substitution;Start=109;End=490
O15151	Motif	442	445	Note=Nuclear localization signal;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Substitution;Start=109;End=490
O15151	Motif	442	445	Note=Nuclear localization signal;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Substitution;Start=109;End=490
O15151	Compositional bias	141	160	Note=Basic and acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=109;End=490
O15151	Compositional bias	141	160	Note=Basic and acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=109;End=490
O15151	Compositional bias	141	160	Note=Basic and acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Deletion;Start=27;End=352

Gene Isoform Structures and Expression Levels for MDM4

Gene structures of our canonical and alternative spliced genes of MDM4
* 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.

Expression levels of gene isoforms across TCGA.

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 O15151-1

3D view using mol* of O15151-2

3D view using mol* of O15151-3

3D view using mol* of O15151-4

3D view using mol* of O15151-5

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 O15151-1

pLDDT distribution across the protein length of O15151-2

pLDDT distribution across the protein length of O15151-3

pLDDT distribution across the protein length of O15151-4

pLDDT distribution across the protein length of O15151-5

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 O15151-1

Ramachandran plot of O15151-4

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
O15151-1	0.83	67	0.862	178.703	0.709	0.556	0.723	0.567	0.739	0.767	1.103	61,62,64,66,68,71,200,201,203,204,205,206,207,208, 209,210,211,212
O15151-2	0.632	36	0.548	81.634	0.65	0.586	0.787	0.072	1.128	0.064	0.575	22,23,24,25,26,108,109,110,111,112
O15151-3	0.596	32	0.546	76.146	0.701	0.549	0.779	0.168	0.966	0.174	0.933	22,23,24,25,26,108,109,110,111
O15151-4	0.668	36	0.646	88.151	0.657	0.57	0.801	0.521	0.799	0.652	2.808	107,108,109,110,118,119,120,131,161,162,163
O15151-5	1.014	171	1.044	452.76	0.58	0.697	1.003	0.907	0.964	0.941	0.934	57,60,61,66,68,69,71,72,74,90,92,93,95,194,197,198 ,200,201,202,203,204,205,206,207,208,209,210,267,2 68,269,271,274

Protein Structure and Feature Comparision

Protein Structure Comparision Using Template Modeling Scores (TM-score).

Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Canonical validated structure (PDB)(green)

3D view using mol* of O15151-1_O15151-1_3fdo_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 O15151-1_3fdo_A_O15151-2.pdb

3D view using mol* of O15151-1_3fdo_A_O15151-3.pdb

3D view using mol* of O15151-1_3fdo_A_O15151-4.pdb

3D view using mol* of O15151-1_3fdo_A_O15151-5.pdb

Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green)

3D view using mol* of O15151-1_O15151-2.pdb

3D view using mol* of O15151-1_O15151-3.pdb

3D view using mol* of O15151-1_O15151-4.pdb

3D view using mol* of O15151-1_O15151-5.pdb

Protein Feature Comparison of the protein sequendary structures among the protiens.

./stats/secondary_structure/figure/O15151-1_vs_O15151-2.png

./stats/secondary_structure/figure/O15151-1_vs_O15151-3.png

./stats/secondary_structure/figure/O15151-1_vs_O15151-4.png

./stats/secondary_structure/figure/O15151-1_vs_O15151-5.png

Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens.

./stats/relative_asa/O15151-1_vs_O15151-2.png

./stats/relative_asa/O15151-1_vs_O15151-3.png

./stats/relative_asa/O15151-1_vs_O15151-4.png

./stats/relative_asa/O15151-1_vs_O15151-5.png

Protein-Protein Interaction

Interactors from UniProt.

Accession_id	Subsection	Start	End	Funcitonal feature	Splicing information
O15151	Region	393	490	Note=Necessary for interaction with USP2;Ontology_term=ECO:0000269;evidence=ECO:0000269\|PubMed:19838211;Dbxref=PMID:19838211	Type=Substitution;Start=109;End=490
O15151	Region	393	490	Note=Necessary for interaction with USP2;Ontology_term=ECO:0000269;evidence=ECO:0000269\|PubMed:19838211;Dbxref=PMID:19838211	Type=Substitution;Start=109;End=490

Interactors from STRING.

Gene name

Interactors

Related Drugs to MDM4

Drugs targeting this gene/protein.
(DrugBank)

UniProt accession

Gene name

DrugBank ID

Drug name

Drug group

Actions

Related Diseases to MDM4

Previous studies relating to the alternative splicing of MDM4 and disease information from the MeSH term (PubMed)

Gene	PMID	Title	Abstract	MeSH ID	MeSH term
MDM4	19273224	MDM2 and MDM4 splicing: an integral part of the cancer spliceome.	MDM2 and MDM4, the murine double minute proteins, are oncogenes that function as important regulators of various proteins. One fundamental role for these proteins is regulation of the tumor suppressor, p53. Precise regulation of p53 is vital for coordinated malignant suppression and cell survival. Alternative splice forms of MDM2 as well as MDM4 have been associated with various cancers. Indeed, UV irradiation triggers alternative splicing of both MDM2 and MDM4. Coordinated alternative splicing in response to cellular stress or in cancerous cells regulates the posttranscriptional expression of these two genes and likely others. This concert of stress responsive mRNAs comprises the cancer spliceome and provides a fingerprint of coordinated alternative splicing in these aberrant cells. Although various transcripts have been described for both proteins, here we provide a precise catalog of the alternatively spliced transcripts of both genes and the cancers with which they are associated.	D009369	Neoplasms
MDM4	23994448	Identification and expression of a novel MDM4 splice variant in human glioma.	The product of the MDMX (or MDM4) gene is structurally related to the MDM2 oncoprotein and is also capable of interacting with the tumor suppressor protein p53. The MDM4 gene is overexpressed in several human tumors, while its product can be detected as various isoforms. This study was aimed to find the presence of aberrant mRNA transcripts of MDM4 in human glioma and their association with the clinicopathological characteristics of glioma patients. 42 glioma tissues were examined for MDM4 mRNA splicing variants by RT-PCR. A total of four distinct transcript sizes (full length-MDM4 851 bp, MDM4-S 783 bp, MDM4-A 701 bp, MDM4-B 540 bp) were detected. In the present study, we first report the novel alternative splicing form of MDM4, MDM4-B (GenBank accession no.KC479043.1). Expression of MDM4-B was present in various stages of human gliomas, but no significant correlation between presence of MDM4-B and malignancy of glioma was observed. The expression level of MDM4-B mRNA detected by real-time PCR was not only significantly associated with tumor stages, but also with p53 mutation and Ki-67 status which are important clinical molecular markers of glioma. Our data indicate that the novel variant MDM4-B may play a role in glioma tumorigenesis or cancer progression.	D005910	Glioma
MDM4	24018792	In vitro and in silico studies of MDM2/MDMX isoforms predict Nutlin-3A sensitivity in well/de-differentiated liposarcomas.	The molecular marker of well-differentiated/de-differentiated liposarcomas is MDM2 gene amplification coupled with protein overexpression and wild-type TP53. MDMX is a recently identified MDM2 homolog and its presence in this tumor is unexplored. Our aim was to investigate the role of full-length MDM2 and MDMX proteins and their isoforms in surgical specimens of well-differentiated/de-differentiated liposarcomas in view of Nutlin-3A (a MDM2 inhibitor) treatment. Frozen and matched formalin-fixed, paraffin-embedded material from surgical specimens was examined by means of: (1) fluorescence in situ hybridization to determine MDM2 and MDMX gene copy numbers; (2) RT-PCR and densitometry to analyze alternative splicing forms of mdm2 and mdmx; (3) immunoblotting and immunohistochemistry to assess the corresponding translated proteins; and (4) in vitro and in silico assays to determine their affinity for Nutlin-3A. All these cases showed MDM2 gene amplification with an MDMX disomic pattern. In all cases, the full-length mdm2 transcript was associated with the mdm2-b transcript, with ratios ranging from 0.07 to 5.6, and both were translated into protein; mdmx and mdmx-s were co-transcripted, with ratios ranging from 0.1 to 5.6. MDMX-S was frequently more upregulated than MDMX at both transcriptional and protein level. Each case showed different amounts of mdm2, mdm2-b, mdmx, and mdmx-s transcripts and the corresponding proteins. In vitro assays showed that Nutlin-3A was ineffective against MDM2-B and was unable to disrupt the MDMX/TP53 and MSMX-S/TP53 complexes. Molecular simulations confirmed these in vitro findings by showing that MDM2 has high Nutlin-3A affinity, followed by MDMX-S, MDMX, and MDM2-B. Nutlin-3A is predicted to be a good therapeutic option for well-differentiated/de-differentiated liposarcomas. However, our findings predict heterogeneous responses depending on the relative expression of mdm2, mdm2-b, mdmx, and mdmx-s transcripts and proteins.	D008080	Liposarcoma
MDM4	24027430	Stress-induced isoforms of MDM2 and MDM4 correlate with high-grade disease and an altered splicing network in pediatric rhabdomyosarcoma.	Pediatric rhabdomyosarcoma (RMS) is a morphologically and genetically heterogeneous malignancy commonly classified into three histologic subtypes, namely, alveolar, embryonal, and anaplastic. An issue that continues to challenge effective RMS patient prognosis is the dearth of molecular markers predictive of disease stage irrespective of tumor subtype. Our study involving a panel of 70 RMS tumors has identified specific alternative splice variants of the oncogenes Murine Double Minute 2 (MDM2) and MDM4 as potential biomarkers for RMS. Our results have demonstrated the strong association of genotoxic-stress inducible splice forms MDM2-ALT1 (91.6% Intergroup Rhabdomyosarcoma Study Group stage 4 tumors) and MDM4-ALT2 (90.9% MDM4-ALT2-positive T2 stage tumors) with high-risk metastatic RMS. Moreover, MDM2-ALT1-positive metastatic tumors belonged to both the alveolar (50%) and embryonal (41.6%) subtypes, making this the first known molecular marker for high-grade metastatic disease across the most common RMS subtypes. Furthermore, our results show that MDM2-ALT1 expression can function by directly contribute to metastatic behavior and promote the invasion of RMS cells through a matrigel-coated membrane. Additionally, expression of both MDM2-ALT1 and MDM4-ALT2 increased anchorage-independent cell-growth in soft agar assays. Intriguingly, we observed a unique coordination in the splicing of MDM2-ALT1 and MDM4-ALT2 in approximately 24% of tumor samples in a manner similar to genotoxic stress response in cell lines. To further explore splicing network alterations with possible relevance to RMS disease, we used an exon microarray approach to examine stress-inducible splicing in an RMS cell line (Rh30) and observed striking parallels between stress-responsive alternative splicing and constitutive splicing in RMS tumors.	D012208	Rhabdomyosarcoma

Clinically important variants in MDM4

(ClinVar, 04/20/2024)

accession_id

uniprot_id

gene_name

Type

Variant

Clinical_significance