UBR4

Summary

UBR4 (ubiquitin protein ligase E3 component n-recognin 4, HGNC:30313) is a protein-coding gene on chromosome 1p36.13, encoding E3 ubiquitin-protein ligase UBR4 (Q5T4S7). E3 ubiquitin-protein ligase involved in different protein quality control pathways in the cytoplasm. It is a common-essential gene (DepMap: required in 92.5% of cancer cell lines).

The protein encoded by this gene is an E3 ubiquitin-protein ligase that interacts with the retinoblastoma-associated protein in the nucleus and with calcium-bound calmodulin in the cytoplasm. The encoded protein appears to be a cytoskeletal component in the cytoplasm and part of the chromatin scaffold in the nucleus. In addition, this protein is a target of the human papillomavirus type 16 E7 oncoprotein.

Source: NCBI Gene 23352 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary episodic ataxia (Moderate, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 694 total — 2 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 92.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_020765

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30313
Approved symbol	UBR4
Name	ubiquitin protein ligase E3 component n-recognin 4
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1307, KIAA0462, RBAF600, p600
Ensembl gene	ENSG00000127481
Ensembl biotype	protein_coding
OMIM	609890
Entrez	23352

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 7 protein_coding_CDS_not_defined, 6 protein_coding, 4 retained_intron

ENST00000375218, ENST00000375224, ENST00000375225, ENST00000375254, ENST00000417040, ENST00000419533, ENST00000425413, ENST00000459947, ENST00000465036, ENST00000466969, ENST00000467272, ENST00000475973, ENST00000483922, ENST00000486515, ENST00000492606, ENST00000494503, ENST00000497018

RefSeq mRNA: 1 — MANE Select: NM_020765 NM_020765

CCDS: CCDS189

Canonical transcript exons

ENST00000375254 — 106 exons

Exon	Start	End
ENSE00001597952	19119557	19119701
ENSE00001600398	19179051	19179220
ENSE00001603717	19192481	19192540
ENSE00001605013	19117823	19117910
ENSE00001605108	19141347	19141524
ENSE00001605576	19093313	19093486
ENSE00001605614	19186540	19186657
ENSE00001605662	19110380	19110464
ENSE00001607720	19124541	19124690
ENSE00001614845	19141647	19141777
ENSE00001624749	19105733	19105842
ENSE00001629636	19114811	19114949
ENSE00001633235	19148563	19148626
ENSE00001633664	19115398	19115637
ENSE00001633679	19112524	19112867
ENSE00001639433	19139083	19139220
ENSE00001642274	19088759	19088977
ENSE00001644195	19192188	19192378
ENSE00001648156	19110742	19110832
ENSE00001652888	19150577	19150793
ENSE00001656936	19105048	19105189
ENSE00001657837	19092819	19092918
ENSE00001659248	19087816	19087929
ENSE00001665479	19127623	19127739
ENSE00001665536	19113945	19114070
ENSE00001667912	19084504	19084698
ENSE00001671083	19193433	19193557
ENSE00001671144	19146826	19147000
ENSE00001675665	19151643	19151859
ENSE00001682752	19183811	19183896
ENSE00001684559	19185099	19185286
ENSE00001687137	19144786	19144907
ENSE00001689519	19198541	19198680
ENSE00001690492	19187441	19187540
ENSE00001690615	19138007	19138181
ENSE00001692291	19113699	19113827
ENSE00001692520	19121934	19122012
ENSE00001695660	19118872	19118957
ENSE00001698917	19201718	19201815
ENSE00001701351	19128978	19129074
ENSE00001713344	19077976	19078066
ENSE00001715525	19197141	19197265
ENSE00001719051	19197670	19197811
ENSE00001720330	19100376	19100573
ENSE00001721044	19120180	19120348
ENSE00001726324	19197947	19198049
ENSE00001736515	19177461	19177743
ENSE00001738143	19086145	19086270
ENSE00001740357	19199651	19199754
ENSE00001743024	19187164	19187301
ENSE00001746555	19121189	19121434
ENSE00001746696	19145793	19145933
ENSE00001749231	19081349	19081573
ENSE00001750464	19122833	19123060
ENSE00001752759	19101520	19101641
ENSE00001761116	19086679	19086821
ENSE00001764812	19106569	19106726
ENSE00001770443	19154918	19155075
ENSE00001779119	19140788	19140892
ENSE00001781319	19198799	19198928
ENSE00001787509	19104585	19104666
ENSE00001792163	19184016	19184175
ENSE00001792909	19143980	19144091
ENSE00001795638	19147993	19148127
ENSE00001796552	19128211	19128318
ENSE00001817757	19210073	19210266
ENSE00001886787	19074510	19074896
ENSE00003458500	19096523	19096650
ENSE00003478357	19099597	19099677
ENSE00003486835	19160917	19161147
ENSE00003503804	19167022	19167231
ENSE00003504670	19173181	19173306
ENSE00003510653	19153768	19153939
ENSE00003517940	19170762	19170883
ENSE00003522319	19165656	19165757
ENSE00003523300	19126446	19126655
ENSE00003523941	19117221	19117414
ENSE00003526129	19094906	19095025
ENSE00003526442	19164799	19164997
ENSE00003528478	19095545	19095652
ENSE00003528740	19164253	19164441
ENSE00003564283	19157815	19157997
ENSE00003578146	19156271	19156423
ENSE00003581932	19174319	19174447
ENSE00003593769	19168027	19168184
ENSE00003596740	19104084	19104257
ENSE00003604643	19173439	19173621
ENSE00003617238	19165249	19165349
ENSE00003618585	19176592	19176727
ENSE00003620123	19156767	19156925
ENSE00003624916	19162420	19162611
ENSE00003626647	19093949	19094139
ENSE00003632435	19106837	19106966
ENSE00003635479	19161589	19161736
ENSE00003645467	19169435	19169532
ENSE00003656891	19161827	19161897
ENSE00003663419	19110096	19110223
ENSE00003667093	19076740	19076902
ENSE00003671824	19097193	19097280
ENSE00003680784	19172864	19173093
ENSE00003681219	19163764	19163827
ENSE00003682461	19153301	19153502
ENSE00003682973	19152313	19152476
ENSE00003683320	19174954	19175033
ENSE00003690806	19160111	19160281
ENSE00003691808	19155441	19155668

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 99.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 108.1535 / max 1320.2105, expressed in 1827 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10642	93.4324	1827
10643	4.7012	1655
10644	4.0889	1616
10631	3.4625	668
10645	1.8479	1168
10646	0.4283	219
10630	0.0613	19
10641	0.0533	9
10638	0.0521	13
10634	0.0197	5

Top tissues by expression

273 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	99.28	gold quality
skin of abdomen	UBERON:0001416	99.17	gold quality
right testis	UBERON:0004534	99.07	gold quality
left testis	UBERON:0004533	99.06	gold quality
mucosa of stomach	UBERON:0001199	98.73	gold quality
lower esophagus mucosa	UBERON:0035834	98.69	gold quality
metanephros cortex	UBERON:0010533	98.33	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.21	gold quality
lower esophagus	UBERON:0013473	98.20	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.17	gold quality
adenohypophysis	UBERON:0002196	98.07	gold quality
stromal cell of endometrium	CL:0002255	98.04	gold quality
apex of heart	UBERON:0002098	97.94	gold quality
right lung	UBERON:0002167	97.80	gold quality
left ovary	UBERON:0002119	97.76	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.71	gold quality
ectocervix	UBERON:0012249	97.68	gold quality
ascending aorta	UBERON:0001496	97.66	gold quality
thoracic aorta	UBERON:0001515	97.64	gold quality
right lobe of liver	UBERON:0001114	97.61	gold quality
body of stomach	UBERON:0001161	97.61	gold quality
ventricular zone	UBERON:0003053	97.58	gold quality
left lobe of thyroid gland	UBERON:0001120	97.57	gold quality
right lobe of thyroid gland	UBERON:0001119	97.55	gold quality
right ovary	UBERON:0002118	97.53	gold quality
body of uterus	UBERON:0009853	97.52	gold quality
left uterine tube	UBERON:0001303	97.41	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.41	gold quality
right frontal lobe	UBERON:0002810	97.40	gold quality
right adrenal gland cortex	UBERON:0035827	97.39	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7381	no	575.75
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting UBR4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-6500-3P	97.42	67.20	867
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-10396B-5P	94.99	63.57	358
HSA-MIR-1908-5P	94.99	63.41	352
HSA-MIR-663A	94.99	63.54	378

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 92.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 14)

• Human papillomavirus E7 oncoprotein associates with p600; interaction strongly contributes to cellular transformation independent of ability of E7 to bind pRB. (PMID:16061792)
• p600 is a cellular target of the human papillomavirus type 16 E7 oncoprotein that regulates cellular pathways that contribute to anchorage-independent growth and cellular transformation. (PMID:16061792)
• Results identify and characterize p600, a unique 600-kDa retinoblastoma protein- and calmodulin-binding protein. (PMID:16214886)
• Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling. (PMID:23555265)
• Although UBR4 is not an ion channel gene, the potential for disrupted Ca(2+) control within neuronal cells highlights its potential for a role in this form of episodic ataxia. (PMID:23982692)
• This review summarizes the central nervous system functions of p600 and proposes new perspectives on its biological complexity in neuronal physiology and neurological diseases. (PMID:25424645)
• Results showed KCMF1 C-terminus binds directly to RAD6, whereas N-terminal domains interact with UBR4 and point mutations found in X-linked intellectual disability (XLID) patients specifically lose the interaction with KCMF1 and UBR4. (PMID:25582440)
• Ubiquitin ligase Ubr4 is a key component of the podocin interactome purified from podocytes. Ubiquitylation of one podocin site, K301, do not only target podocin for proteasomal degradation, but may also affect stability and disassembly of the multimeric complex. (PMID:26792178)
• Pathogenic mutation in UBR4 gene is associated with Episodic Ataxia. (PMID:29062094)
• The endosomal recruitment of UBR4 is essential for the biogenesis of early endosomes and endosome-related processes. (PMID:30111582)
• A new 1p36.13-1p36.12 microdeletion syndrome characterized by learning disability, behavioral abnormalities, and ptosis. (PMID:32170730)
• UBR E3 ligases and the PDIA3 protease control degradation of unfolded antibody heavy chain by ERAD. (PMID:32558906)
• Rift Valley fever virus Gn V5-epitope tagged virus enables identification of UBR4 as a Gn interacting protein that facilitates Rift Valley fever virus production. (PMID:35032865)
• IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease. (PMID:38885295)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ubr4	ENSDARG00000009549
mus_musculus	Ubr4	ENSMUSG00000066036
rattus_norvegicus	Ubr4	ENSRNOG00000018183
drosophila_melanogaster	poe	FBGN0011230
caenorhabditis_elegans	ubr-4	WBGENE00016650

Protein

Protein identifiers

E3 ubiquitin-protein ligase UBR4 — Q5T4S7 (reviewed: Q5T4S7)

Alternative names: 600 kDa retinoblastoma protein-associated factor, N-recognin-4, Retinoblastoma-associated factor of 600 kDa

All UniProt accessions (5): Q5T4S7, A0A0A0MSW0, Q5TBN9, X6R960, X6RE05

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase involved in different protein quality control pathways in the cytoplasm. Component of the N-end rule pathway: ubiquitinates proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their degradation. Recognizes both type-1 and type-2 N-degrons, containing positively charged amino acids (Arg, Lys and His) and bulky and hydrophobic amino acids, respectively. Does not ubiquitinate proteins that are acetylated at the N-terminus. Together with UBR5, part of a cytoplasm protein quality control pathway that prevents protein aggregation by catalyzing assembly of heterotypic ‘Lys-11’-/‘Lys-48’-linked branched ubiquitin chains on aggregated proteins, leading to substrate recognition by the segregase p97/VCP and degradation by the proteasome: UBR4 probably synthesizes mixed chains containing multiple linkages, while UBR5 is likely branching multiple ‘Lys-48’-linked chains of substrates initially modified. Together with KCMF1, part of a protein quality control pathway that catalyzes ubiquitination and degradation of proteins that have been oxidized in response to reactive oxygen species (ROS): recognizes proteins with an Arg-CysO3(H) degron at the N-terminus, and mediates assembly of heterotypic ‘Lys-63’-/‘Lys-27’-linked branched ubiquitin chains on oxidized proteins, leading to their degradation by autophagy. Catalytic component of the SIFI complex, a multiprotein complex required to inhibit the mitochondrial stress response after a specific stress event has been resolved: ubiquitinates and degrades (1) components of the HRI-mediated signaling of the integrated stress response, such as DELE1 and EIF2AK1/HRI, as well as (2) unimported mitochondrial precursors. Within the SIFI complex, UBR4 initiates ubiquitin chain that are further elongated or branched by KCMF1. Mediates ubiquitination of ACLY, leading to its subsequent degradation. Together with clathrin, forms meshwork structures involved in membrane morphogenesis and cytoskeletal organization.

Subunit / interactions. Component of the SIFI complex, composed of KCMF1, UBR4 and calmodulin (CALM1, CALM2 or CALM3). Interacts with E2 conjugating enzymes UBE2A and UBE2B. Interacts with RB1. (Microbial infection) Interacts with protein E7 from papilloma virus HPV-16, HPV-6B and HPV-11. (Microbial infection) Interacts with Rift valley fever virus glycoprotein N; this interaction is important for viral RNA production.

Subcellular location. Cytoplasm. Cytoskeleton. Nucleus.

Disease relevance. Episodic ataxia 8 (EA8) [MIM:616055] A form of episodic ataxia, a neurologic disorder characterized by episodes of poor coordination and balance. EA8 affected individuals have attacks of unsteadiness, general weakness, and slurred speech. Additional variable features include twitching around the eyes, nystagmus, myokymia, and persistent intention tremor. Inheritance is autosomal dominant. The gene represented in this entry may be involved in disease pathogenesis.

Domain organisation. The UBR-type zinc finger forms a pocket that mediates recognition of type 1 N-degrons. It can also recognize type-2 N-degrons via two phenylalanines, Phe-1671 and Phe-1713, on its hydrophobic surface. In addition to substrate-binding, the UBR-type zinc finger probably positions substrate proteins in the proximity of the bound and activated E2-ubiquitin conjugate to enable their ubiquitination. Constitutes an atypical E3 ubiquitin-protein ligase composed of a hemiRING-type zinc finger, a UBR-type zinc-finger interacting subdomain (UZI) and an N-terminal region that can serve as an affinity factor for the E2 conjugating enzymes UBE2A and UBE2B. Compared to classical RING-type, the hemiRING-type only binds a single zinc ion: a hydrogen bonding network is present instead of a second zinc ion. The hemiRING-type zinc finger maintains specificity for E2 conjugating enzymes UBE2A and UBE2B, which have high intrinsic lysine reactivity, obviating the need for the robust thioester activation of classical RING-type E3 ubiquitin-protein ligases.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the UBR4 family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q5T4S7-1	1	yes
Q5T4S7-2	2
Q5T4S7-3	3
Q5T4S7-4	4
Q5T4S7-5	5
Q5T4S7-6	6

RefSeq proteins (1): NP_065816* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003126	Znf_UBR	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR025704	E3_Ub_ligase_UBR4_C	Domain
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR045189	UBR4-like	Family
IPR045841	E3_UBR4_N	Domain
IPR047509	UBR4-like_UBR-box	Domain
IPR056530	UBR4-like_dom	Domain

Pfam: PF02207, PF13764, PF19423, PF24079

UniProt features (126 total): modified residue 20, helix 18, binding site 16, compositionally biased region 14, turn 10, splice variant 10, region of interest 9, strand 8, mutagenesis site 7, sequence variant 6, sequence conflict 4, zinc finger region 2, chain 1, domain 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
8J9R	X-RAY DIFFRACTION	1.65
8B5W	X-RAY DIFFRACTION	1.8
8J9Q	X-RAY DIFFRACTION	2.18
9HXW	ELECTRON MICROSCOPY	3.1
9QWS	ELECTRON MICROSCOPY	3.1
9QWU	ELECTRON MICROSCOPY	3.1
8BTL	X-RAY DIFFRACTION	3.2
9NWE	ELECTRON MICROSCOPY	3.2
9D9Z	ELECTRON MICROSCOPY	3.4
9NWD	ELECTRON MICROSCOPY	3.4
9QX0	ELECTRON MICROSCOPY	3.4
9QWX	ELECTRON MICROSCOPY	3.6
9QWZ	ELECTRON MICROSCOPY	4.8

Predicted structure (AlphaFold)

No AlphaFold model available for Q5T4S7 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (16): 1662; 1679; 1682; 1691; 1694; 1694; 1698; 1699; 1702; 1714; 1716; 1724 …

Post-translational modifications (20): 178, 181, 212, 370, 905, 1084, 1402, 1647, 1652, 1747, 1754, 1763, 1878, 1904, 2715, 2719, 2722, 2724, 2944, 2952

Mutagenesis-validated functional residues (7):

Position	Phenotype
1670	does not affect ability to recognize type-2 n-degrons.
1671	does not recognize type-2 n-degrons.
1712	reduced but not abolished ability to recognize type-2 n-degrons.
1713	does not recognize type-2 n-degrons.
4841	abolished e3 ubiquitin-protein ligase activity.
4843	abolished e3 ubiquitin-protein ligase activity.
4890	abolished e3 ubiquitin-protein ligase activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses

MSigDB gene sets: 0 (showing top):

GO Biological Process (26): ubiquitin-dependent protein catabolic process (GO:0006511), protein quality control for misfolded or incompletely synthesized proteins (GO:0006515), response to oxidative stress (GO:0006979), endosome organization (GO:0007032), positive regulation of autophagy (GO:0010508), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), protein K27-linked ubiquitination (GO:0044314), negative regulation of fatty acid biosynthetic process (GO:0045717), protein stabilization (GO:0050821), protein K48-linked ubiquitination (GO:0070936), protein K11-linked ubiquitination (GO:0070979), ubiquitin-dependent protein catabolic process via the N-end rule pathway (GO:0071596), cytoplasm protein quality control by the ubiquitin-proteasome system (GO:0071629), cytoplasm protein quality control (GO:0140455), negative regulation of HRI-mediated signaling (GO:0141191), protein branched polyubiquitination (GO:0141198), cytoplasmic translation (GO:0002181), translational initiation (GO:0006413), fatty acid biosynthetic process (GO:0006633), proteasomal protein catabolic process (GO:0010498), protein ubiquitination (GO:0016567), protein catabolic process (GO:0030163), cellular response to stress (GO:0033554), type I interferon-mediated signaling pathway (GO:0060337), protein targeting to vacuole involved in autophagy (GO:0071211), HRI-mediated signaling (GO:0140468)

GO Molecular Function (8): ubiquitin-protein transferase activity (GO:0004842), calmodulin binding (GO:0005516), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (10): nucleus (GO:0005634), cytoplasm (GO:0005737), endosome (GO:0005768), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020), specific granule membrane (GO:0035579), tertiary granule membrane (GO:0070821), ficolin-1-rich granule membrane (GO:0101003)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Innate Immune System	1
Class I MHC mediated antigen processing & presentation	1
Dengue Virus-Host Interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein polyubiquitination	4
cellular anatomical structure	3
secretory granule membrane	3
protein catabolic process	2
proteasome-mediated ubiquitin-dependent protein catabolic process	2
translation	2
tertiary granule	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
response to stress	1
endomembrane system organization	1
vesicle organization	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
fatty acid biosynthetic process	1
regulation of fatty acid biosynthetic process	1
negative regulation of fatty acid metabolic process	1
negative regulation of lipid biosynthetic process	1
regulation of protein stability	1
cellular response to misfolded protein	1
cytoplasm protein quality control	1
protein quality control for misfolded or incompletely synthesized proteins	1
biological regulation	1
formation of translation initiation ternary complex	1
metabolic process	1
fatty acid metabolic process	1
lipid biosynthetic process	1
monocarboxylic acid biosynthetic process	1
ubiquitin-like protein transferase activity	1
protein binding	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
enzyme-substrate adaptor activity	1
binding	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

1835 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UBR4	CALML6	Q8TD86	891
UBR4	CALML3	P27482	891
UBR4	CALML4	Q96GE6	891
UBR4	CALML5	Q9NZT1	891
UBR4	CALM1	P02593	890
UBR4	UBR1	Q8IWV7	871
UBR4	UBR2	Q8IWV8	871
UBR4	KCMF1	Q9P0J7	864
UBR4	RBL2	Q08999	730
UBR4	HUWE1	Q7Z6Z7	674
UBR4	ATE1	O95260	663
UBR4	STAT2	P52630	640
UBR4	RNF181	Q9P0P0	617
UBR4	UBE3C	Q15386	610
UBR4	UBR5	O95071	595

IntAct

214 interactions, top by confidence:

A	B	Type	Score
PIK3CA	PIK3R2	psi-mi:“MI:0914”(association)	0.900
NRP1	CSNK2A2	psi-mi:“MI:0914”(association)	0.790
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
KCMF1	UBR4	psi-mi:“MI:0915”(physical association)	0.710
E7	RB1	psi-mi:“MI:0914”(association)	0.700
FOXK2	DVL2	psi-mi:“MI:0914”(association)	0.640
VEGFD	ADAM9	psi-mi:“MI:0914”(association)	0.640
NME3	NME4	psi-mi:“MI:0914”(association)	0.640
CHEK2	PPM1G	psi-mi:“MI:0914”(association)	0.560
	UBR4	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	UBR4	psi-mi:“MI:0915”(physical association)	0.560
ORF	EIF3F	psi-mi:“MI:0914”(association)	0.560
UBR4	UBE2A	psi-mi:“MI:0915”(physical association)	0.550
UBR4	UBE2B	psi-mi:“MI:0915”(physical association)	0.550
UBR4	UBE2A	psi-mi:“MI:0914”(association)	0.550
FAF2	PJA2	psi-mi:“MI:0914”(association)	0.530
TFDP3	E2F3	psi-mi:“MI:0914”(association)	0.530
ELP2	DNAJA2	psi-mi:“MI:0914”(association)	0.530

BioGRID (468): ACLY (Affinity Capture-Western), UBR4 (Affinity Capture-Western), UBR4 (Affinity Capture-RNA), UBR4 (Affinity Capture-RNA), UBR4 (Affinity Capture-RNA), UBR4 (Affinity Capture-MS), UBR4 (Affinity Capture-Western), UBR4 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), UBR4 (Affinity Capture-MS)

ESM2 similar proteins: A0A120KVR5, A0A120KVR8, A0A120KVW2, A2AN08, A8E1C4, B5APK2, B9VXQ2, C5DCN9, D5LX59, F5HC79, F5HEA3, F5HEN8, O04064, O41253, P09275, P16724, P16736, P16784, P16801, P16823, P17958, P24438, P24653, P34335, P42286, Q18892, Q29L39, Q2HR92, Q2TL32, Q384Y0, Q40504, Q57XV5, Q5T4S7, Q6B9Y8, Q6CAD2, Q6SW48, Q6SW85, Q6UDK0, Q6V3W0, Q751J3

Diamond homologs: A2AN08, O95071, P51592, Q29L39, Q2TL32, Q5T4S7, Q62671, Q7TPD1, Q7TSL3, Q80TP3, Q86XK2, Q94251, Q9VLT5, A1CRM1, A1D4K4, A2A5N3, A4QUF0, B9G2A8, D3ZBM7, E1C656, F1N6G5, F1QB54, F8W2M1, O22173, O64380, P0CP46, P0CP47, P11940, P20965, P21187, P29341, P31209, P42731, P61286, Q05196, Q0CR95, Q0U1G2, Q13310, Q1DXH0, Q28BK1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
UBR4	“down-regulates quantity by destabilization”	TRPV5	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 230 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Transcriptional Regulation by MECP2	6	12.5×	6e-03
PI3K Cascade	6	10.7×	8e-03
Constitutive Signaling by Aberrant PI3K in Cancer	8	6.7×	8e-03
RAF/MAP kinase cascade	11	4.4×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	16	4.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

694 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	458
Likely benign	83
Benign	50

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
599501	NM_020765.3(UBR4):c.7031A>G (p.Asn2344Ser)	Likely pathogenic
599552	NM_020765.3(UBR4):c.6325G>A (p.Gly2109Ser)	Likely pathogenic

SpliceAI

15105 predictions. Top by Δscore:

Variant	Effect	Δscore
1:19076735:CTAA:C	donor_loss	1.0000
1:19076736:TAA:T	donor_loss	1.0000
1:19076737:AACCG:A	donor_loss	1.0000
1:19076738:A:AC	donor_gain	1.0000
1:19076738:ACCGG:A	donor_gain	1.0000
1:19076739:C:CA	donor_loss	1.0000
1:19076739:C:CC	donor_gain	1.0000
1:19076739:CCGG:C	donor_gain	1.0000
1:19076739:CCGGC:C	donor_gain	1.0000
1:19076787:T:TA	donor_gain	1.0000
1:19076898:ACCTT:A	acceptor_gain	1.0000
1:19076899:CCTTC:C	acceptor_gain	1.0000
1:19076900:CTT:C	acceptor_gain	1.0000
1:19076901:TT:T	acceptor_gain	1.0000
1:19076903:C:CC	acceptor_gain	1.0000
1:19076904:T:A	acceptor_loss	1.0000
1:19076906:C:CT	acceptor_gain	1.0000
1:19076907:G:T	acceptor_gain	1.0000
1:19076913:C:CT	acceptor_gain	1.0000
1:19076914:A:T	acceptor_gain	1.0000
1:19076916:C:CT	acceptor_gain	1.0000
1:19076917:A:T	acceptor_gain	1.0000
1:19081572:TT:T	acceptor_gain	1.0000
1:19081574:C:CC	acceptor_gain	1.0000
1:19084502:A:AC	donor_gain	1.0000
1:19084503:C:CC	donor_gain	1.0000
1:19084694:TGTGT:T	acceptor_gain	1.0000
1:19084695:GTGT:G	acceptor_gain	1.0000
1:19084696:TGT:T	acceptor_gain	1.0000
1:19084697:GT:G	acceptor_gain	1.0000

AlphaMissense

34075 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:19084554:G:C	N4986K	1.000
1:19084554:G:T	N4986K	1.000
1:19084570:C:T	G4981D	1.000
1:19084573:C:T	G4980E	1.000
1:19086160:G:T	A4933D	1.000
1:19086178:A:T	V4927D	1.000
1:19086187:C:T	G4924E	1.000
1:19086188:C:G	G4924R	1.000
1:19086188:C:T	G4924R	1.000
1:19086196:G:C	P4921R	1.000
1:19086196:G:T	P4921Q	1.000
1:19086199:A:G	L4920P	1.000
1:19086202:A:G	L4919P	1.000
1:19086205:C:T	G4918E	1.000
1:19086206:C:A	G4918W	1.000
1:19086206:C:G	G4918R	1.000
1:19086206:C:T	G4918R	1.000
1:19086207:G:C	N4917K	1.000
1:19086207:G:T	N4917K	1.000
1:19086210:G:C	C4916W	1.000
1:19086211:C:T	C4916Y	1.000
1:19086212:A:G	C4916R	1.000
1:19086225:A:C	N4911K	1.000
1:19086225:A:T	N4911K	1.000
1:19086226:T:A	N4911I	1.000
1:19086226:T:G	N4911T	1.000
1:19086227:T:C	N4911D	1.000
1:19086227:T:G	N4911H	1.000
1:19086232:A:G	L4909P	1.000
1:19086232:A:T	L4909Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000005995 (1:19119222 T>C), RS1000006027 (1:19074661 G>A), RS1000015144 (1:19208321 G>C), RS1000017136 (1:19140293 A>C), RS1000058657 (1:19164543 T>C), RS1000058732 (1:19176111 T>C), RS1000065554 (1:19095157 T>A,C), RS1000067008 (1:19163520 T>C), RS1000072009 (1:19140556 TG>T), RS1000088939 (1:19086343 C>G,T), RS1000100746 (1:19192086 A>C,G), RS1000102155 (1:19074375 C>A,T), RS1000104443 (1:19150525 G>A,T), RS1000112567 (1:19143147 AGAAGGAAGGGAAAGGAAAG>A), RS1000114568 (1:19158326 C>G)

Disease associations

OMIM: gene MIM:609890 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary episodic ataxia	Moderate	Autosomal dominant

Mondo (4): neurodevelopmental disorder (MONDO:0700092), long QT syndrome (MONDO:0002442), premature menopause (MONDO:0001119), hereditary episodic ataxia (MONDO:0016227)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007001_1	Cerebrospinal AB1-42 levels in normal cognition	5.000000e-07
GCST008572_4	Composite immunoglobulin trait (IgA/IgG)	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004670	beta-amyloid 1-42 measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL4295851 (SINGLE PROTEIN), CHEMBL6193829 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193830 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.44	Kd	3.662	nM	CHEMBL3752910
8.44	ED50	3.662	nM	CHEMBL3752910
6.23	Kd	593	nM	CHEMBL5653589
6.23	ED50	593	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 6 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149718: Binding affinity to human UBR4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0037	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149718: Binding affinity to human UBR4 incubated for 45 mins by Kinobead based pull down assay	kd	0.5930	uM

CTD chemical–gene interactions

62 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Benzo(a)pyrene	increases mutagenesis, decreases methylation, increases expression	3
Tobacco Smoke Pollution	decreases methylation, increases expression	2
Tunicamycin	increases expression	2
Cyclosporine	increases expression	2
Aflatoxin B1	increases expression, increases methylation, decreases methylation	2
Cadmium Chloride	increases abundance, increases palmitoylation, increases expression, decreases reaction	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation, affects cotreatment	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	increases expression	1
2-bromopalmitate	increases abundance, increases palmitoylation, decreases reaction	1
manganese chloride	decreases expression, increases abundance	1
coumarin	affects phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
tebuconazole	decreases expression	1
CGP 52608	increases reaction, affects binding	1
bazedoxifene	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
bisphenol S	decreases methylation	1
LDN 193189	decreases expression, affects cotreatment	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118664	Binding	Binding affinity to UBR4 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9VD	Ubigene HEK293 UBR4 KO	Transformed cell line	Female

Clinical trials (associated diseases)

302 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials