STUB1

Summary

STUB1 (STIP1 homology and U-box containing protein 1, HGNC:11427) is a protein-coding gene on chromosome 16p13.3, encoding E3 ubiquitin-protein ligase CHIP (Q9UNE7). E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation.

This gene encodes a protein containing tetratricopeptide repeat and a U-box that functions as a ubiquitin ligase/cochaperone. The encoded protein binds to and ubiquitinates shock cognate 71 kDa protein (Hspa8) and DNA polymerase beta (Polb), among other targets. Mutations in this gene cause spinocerebellar ataxia, autosomal recessive 16. Alternative splicing results in multiple transcript variants. There is a pseudogene for this gene on chromosome 2.

Source: NCBI Gene 10273 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive spinocerebellar ataxia 16 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 141 total — 12 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 76
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_005861

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11427
Approved symbol	STUB1
Name	STIP1 homology and U-box containing protein 1
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	UBOX1, CHIP, SDCCAG7, HSPABP2, NY-CO-7
Ensembl gene	ENSG00000103266
Ensembl biotype	protein_coding
OMIM	607207
Entrez	10273

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000219548, ENST00000563505, ENST00000564316, ENST00000564370, ENST00000565677, ENST00000565813, ENST00000566181, ENST00000566408, ENST00000567173, ENST00000567790, ENST00000569248, ENST00000880076, ENST00000880077, ENST00000880078, ENST00000880079, ENST00000917532, ENST00000965393

RefSeq mRNA: 2 — MANE Select: NM_005861 NM_001293197, NM_005861

CCDS: CCDS10419, CCDS76797

Canonical transcript exons

ENST00000219548 — 7 exons

Exon	Start	End
ENSE00000664210	681793	681880
ENSE00001061965	680410	680684
ENSE00002606823	682364	682801
ENSE00003500668	682165	682281
ENSE00003618126	681152	681350
ENSE00003653425	682020	682076
ENSE00003673003	681438	681603

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 69.9534 / max 565.2428, expressed in 1827 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151970	67.2964	1827
151969	2.3554	1263
151971	0.3017	137

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	99.57	gold quality
postcentral gyrus	UBERON:0002581	99.45	gold quality
parietal lobe	UBERON:0001872	99.42	gold quality
substantia nigra pars compacta	UBERON:0001965	99.38	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.36	gold quality
lateral globus pallidus	UBERON:0002476	99.36	gold quality
dorsal root ganglion	UBERON:0000044	99.28	gold quality
superior vestibular nucleus	UBERON:0007227	99.24	gold quality
ventral tegmental area	UBERON:0002691	99.20	gold quality
adult organism	UBERON:0007023	99.19	gold quality
parotid gland	UBERON:0001831	99.18	gold quality
pons	UBERON:0000988	99.16	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.13	gold quality
nipple	UBERON:0002030	99.08	gold quality
trigeminal ganglion	UBERON:0001675	98.95	gold quality
renal medulla	UBERON:0000362	98.94	gold quality
inferior vagus X ganglion	UBERON:0005363	98.88	gold quality
body of tongue	UBERON:0011876	98.87	gold quality
superior frontal gyrus	UBERON:0002661	98.85	gold quality
entorhinal cortex	UBERON:0002728	98.84	gold quality
pylorus	UBERON:0001166	98.83	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.78	gold quality
cardia of stomach	UBERON:0001162	98.77	gold quality
subthalamic nucleus	UBERON:0001906	98.73	gold quality
seminal vesicle	UBERON:0000998	98.68	gold quality
biceps brachii	UBERON:0001507	98.68	gold quality
prefrontal cortex	UBERON:0000451	98.65	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.58	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.57	gold quality
pharyngeal mucosa	UBERON:0000355	98.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	212.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AKT1, ESR2, TP53, VDR, ZNF143

miRNA regulators (miRDB)

8 targeting STUB1, 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-4672	99.50	71.58	2893
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-6783-5P	97.67	67.21	1528
HSA-MIR-4690-3P	97.02	64.72	981
HSA-MIR-5685	97.02	64.34	1004

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Ubiquitin ligases (u box) determine protein stability in a highly regulated manner by coordinating the addition of polyubiquitin chains to proteins that are then targeted to the proteasome for degradation. (PMID:11805346)
• Chip overexpression reduced the rate of AR degradation, consistent with an effect on AR folding,Chip affected AR folding was further supported by the finding that the effects of exogenous Chip were reproduced by a mutant lacking the U box (PMID:12559985)
• CHIP E3 controls both the association of Hsp70/Hsp90 chaperones with ErbB2 and the down-regulation of ErbB2 induced by inhibitors of Hsp90 (PMID:12574167)
• tau binds to Hsc70, and its phosphorylation is a recognition requirement for the addition of ubiquitin by the E3 Ub ligase CHIP (PMID:14612456)
• CHIP can interact with the Smad1/Smad4 proteins and block BMP signal transduction through the ubiquitin-mediated degradation of Smad proteins. (PMID:14701756)
• Hsp70/CHIP may play an important role in the pathogenesis of tauopathies (PMID:14962978)
• In cells treated with dexamethasone and geldanamycin, the GFP-GR becomes concentrated in fluorescent globules located periodically along the neurites. CHIP protein concentrates in the same loci in a steroid-dependent and geldanamycin-dependent manner. (PMID:15046863)
• CHIP functions as a negative regulator of AR transcriptional activity by promoting AR degradation (PMID:15107424)
• HspBP1 interferes with the CHIP-induced degradation of immature forms of the cystic fibrosis transmembrane conductance regulator (CFTR) and stimulates CFTR maturation. (PMID:15215316)
• Results suggest that co-chaperone CHIP, possibly with another E3 ligase(s), modulates the ubiquitylation of mutant Cu/Zn-superoxide dismutase and renders them more susceptible for proteasomal degradation. (PMID:15358145)
• CHIP is an E3 ligase for nNOS whose action is facilitated by (and possibly requires) its interaction with nNOS-bound hsp70 (PMID:15466472)
• CHIP is an E3 ligase that mediates alternative effects of the ubiquitin-proteasome pathway on glucocorticoid receptor down-regulation and transactivation (PMID:15761032)
• findings suggest that CHIP can modulate the sensitivity of the TGF-beta signaling by controlling the basal level of Smad3 through ubiquitin-mediated degradation (PMID:15781469)
• CHIP-induced degradation was observed for mutant and wild-type p53, which transiently associate with molecular chaperones Hsc70 and Hsp90 and can be diverted onto a degradation pathway through this association (PMID:15911628)
• CHIP promotes ERalpha degradation and attenuates receptor-mediated gene transcription. (PMID:16037132)
• Increases in CHIP may protect against neurofibrillary tangles formation in the early stages of Alzheimer’s disease. (PMID:16111477)
• Hsc70 cochaperone BAG-2 as a main component of CHIP complexes. BAG-2 inhibits the ubiquitin ligase activity of CHIP. (PMID:16207813)
• CHIP directly interacts with C-terminal deleted HSF1 but not with full-length HSF1 under non-stressed conditions, and with full-length HSF1 under heat shock treatment; interaction requires conformational change of HSF1 by heat stress. (PMID:16293251)
• CHIP is identified as a functional partner of Ubc13-Uev1a in formation of Lys63-linked polyubiquitin chains, extending CHIP’s roles into ubiquitin regulation as well as targeted destruction. (PMID:16307917)
• Chip may be at least one ubiquitin E3 ligase responsible for eIF4E ubiquitination (PMID:16720573)
• CHIP recognizes AR in a highly specific, phosphorylation- and sequence-dependent manner (PMID:16725394)
• Results show that CHIP and ataxin-1 proteins directly interact and co-localize in nuclear inclusions both in cell culture and spinocerebellar ataxia type-1 postmortem neurons. (PMID:16831871)
• Our findings suggest that the role of CHIP in aggregation of polyQ proteins greatly varies depending on the context of full-length polyQ proteins. (PMID:17127076)
• Dorfin-CHIP(L) rescued neuronal cells from mutant SOD1-associated toxicity and reduced the aggresome formation induced by mutant SOD1 more effectively than did Dorfin(WT). (PMID:17157513)
• A critical mediator of Hsp90 inhibition leading to p-tau degradation is CHIP. (PMID:17304350)
• DAPK is found in two distinct immune complexes, one containing HSP90 and CHIP and a second complex containing only DIP1/Mib; strict modulation of DAPK activities by HSP90 heterocomplexes is critical for regulation of apoptosis and cellular homeostasis (PMID:17324930)
• CHIP possesses an intrinsic chaperone activity that enables it to selectively recognize and bind nonnative proteins (PMID:17545168)
• CHIP might be a direct chaperone of wild type p53 that helps p53 in maintaining wild type conformation under physiological condition as well as help resurrect p53 mutant phenotype into a folded native state under stress condition. (PMID:17666403)
• Ubiquitin ligase activity of CHIP is dispensable for Tal1/SCL binding but essential for degradation. (PMID:17962192)
• CHIP might preferentially regulate phosphorylated Smad1 and thus the BMP signaling (PMID:17963781)
• These results indicate that the MKKS mutants have an abnormal conformation and that chaperone-dependent degradation mediated by CHIP is a key feature of McKusick-Kaufman syndrome/Bardet-Biedl syndrome diseases. (PMID:18094050)
• Data show that CHIP-mediated degradation and DNA damage-dependent stabilization regulate base excision repair proteins XRCC1, DNA polymerase beta, and DNA ligase III. (PMID:18313385)
• CHIP preferentially recognizes and mediates degradation of toxic, oligomeric forms of alphaSyn (PMID:18436529)
• Inhibition of tyrosine kinase activity of Her-2/neu by quercetin could indicate an lateration in the Her-2/neu structure which promotes CHIP recruitments and down-regulation of Her-2/neu (PMID:18655187)
• Wild type CHIP induces mitotic abnormity in K562 cells. (PMID:18718056)
• Function of deletion mutant shows that E3 ubiquitin ligases function redundantly. (PMID:18784277)
• This study reveals a critical role for CHIP in the aggresome pathway. (PMID:18955503)
• Overexpression of CHIP protects mammalian cells from ricin intoxication by ubiquitylating ricin A chin in the context of Hsp90 binding. (PMID:18988734)
• Csp not only regulates the exit of CFTR from the ER, but that this action is accompanied by Hsc70/Hsp70 and CHIP-mediated CFTR degradation. (PMID:19098309)
• both UBC7/gp78 and UbcH5a/CHIP may be involved in CYP3A4 ER-associated degradation, although their relative physiological contribution remains to be established (PMID:19103148)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	stub1	ENSDARG00000045228
mus_musculus	Stub1	ENSMUSG00000039615
rattus_norvegicus	Stub1	ENSRNOG00000019798
drosophila_melanogaster	STUB1	FBGN0027052
caenorhabditis_elegans	chn-1	WBGENE00000500

Paralogs (18): RPAP3 (ENSG00000005175), TOMM34 (ENSG00000025772), ST13 (ENSG00000100380), SPAG1 (ENSG00000104450), SGTA (ENSG00000104969), TTC1 (ENSG00000113312), TTC31 (ENSG00000115282), UNC45A (ENSG00000140553), UNC45B (ENSG00000141161), SPATA16 (ENSG00000144962), TTC12 (ENSG00000149292), TOMM70 (ENSG00000154174), SUGT1 (ENSG00000165416), STIP1 (ENSG00000168439), TTC32 (ENSG00000183891), SGTB (ENSG00000197860), TTC4 (ENSG00000243725), DNAAF4 (ENSG00000256061)

Protein

Protein identifiers

E3 ubiquitin-protein ligase CHIP — Q9UNE7 (reviewed: Q9UNE7)

Alternative names: Antigen NY-CO-7, CLL-associated antigen KW-8, Carboxy terminus of Hsp70-interacting protein, RING-type E3 ubiquitin transferase CHIP, STIP1 homology and U box-containing protein 1

All UniProt accessions (5): Q9UNE7, H3BS86, H3BTA3, H3BUD0, V9GYH3

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation. Plays a role in the maintenance of mitochondrial morphology and promotes mitophagic removal of dysfunctional mitochondria; thereby acts as a protector against apoptosis in response to cellular stress. Negatively regulates vascular smooth muscle contraction, via degradation of the transcriptional activator MYOCD and subsequent loss of transcription of genes involved in vascular smooth muscle contraction. Promotes survival and proliferation of cardiac smooth muscle cells via ubiquitination and degradation of FOXO1, resulting in subsequent repression of FOXO1-mediated transcription of pro-apoptotic genes. Ubiquitinates ICER-type isoforms of CREM and targets them for proteasomal degradation, thereby acts as a positive effector of MAPK/ERK-mediated inhibition of apoptosis in cardiomyocytes. Inhibits lipopolysaccharide-induced apoptosis and hypertrophy in cardiomyocytes, via ubiquitination and subsequent proteasomal degradation of NFATC3. Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. Ubiquitinates NOS1 in concert with Hsp70 and Hsp40. Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90. Ubiquitinates CHRNA3 targeting it for endoplasmic reticulum-associated degradation in cortical neurons, as part of the STUB1-VCP-UBXN2A complex. Ubiquitinates and promotes ESR1 proteasomal degradation in response to age-related circulating estradiol (17-beta-estradiol/E2) decline, thereby promotes neuronal apoptosis in response to ischemic reperfusion injury. Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation. Mediates polyubiquitination of DNA polymerase beta (POLB) at ‘Lys-41’, ‘Lys-61’ and ‘Lys-81’, thereby playing a role in base-excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB-degradation by the proteasome. Mediates polyubiquitination of CYP3A4. Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation. Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and promotes ubiquitin-mediated protein degradation. Negatively regulates the suppressive function of regulatory T-cells (Treg) during inflammation by mediating the ubiquitination and degradation of FOXP3 in a HSPA1A/B-dependent manner. Catalyzes monoubiquitination of SIRT6, preventing its degradation by the proteasome. Likely mediates polyubiquitination and down-regulates plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. Negatively regulates TGF-beta signaling by modulating the basal level of SMAD3 via ubiquitin-mediated degradation. Plays a role in the degradation of TP53. Mediates ubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation. May regulate myosin assembly in striated muscles together with UBE4B and VCP/p97 by targeting myosin chaperone UNC45B for proteasomal degradation. Ubiquitinates PPARG in macrophages playing a role in M2 macrophages polarization and angiogenesis.

Subunit / interactions. Homodimer. Interacts with BAG2. Interacts with E2 ubiquitin conjugating enzymes UBE2D1, UBE2D2 and UBE2D3. Detected in a ternary complex containing STUB1, HSPA1A and HSPBP1. Part of a complex composed of STUB1/CHIP, VCP/p97, CHRNA3, and UBXN2A that modulates the ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of CHRNA3. Within the complex UBXN2A acts as a scaffold protein required for the interaction of CHRNA3 with VCP/p97, this interaction also inhibits CHRNA3 ubiquitination by STUB1/CHIP and subsequently ERAD. Interacts with MKKS. Interacts with DNAAF4. Interacts (when monoubiquitinated) with ATXN3. Interacts with UBE2W. Interacts (via the U-box domain) with the UBE2V2-UBE2N heterodimer; the complex has a specific ‘Lys-63’-linked polyubiquitination activity. Interacts with DNAJB6. Interacts with FLCN. Interacts with HSP90AA1. Interacts with HSP90. Interacts with UBE2N and UBE2V1. Interacts (via TPR repeats) with HSPA8 (via C-terminus). Interacts (via TPR repeats) with HSPA1A (via C-terminus). Interacts with the non-acetylated form of HSPA1A and HSPA1B. Interacts with SMAD3 and HSP90AB1. Interacts with UBE4B. Interacts with PRMT5. Interacts with MYOCD (via C-terminus). Interacts with FOXO1 (when phosphorylated on ‘Ser-256’). Interacts with MAPK7/ERK5; the interaction is enhanced in the presence of IGF1 or MAP2K5 and promotes STUB1/CHIP E3 ligase activity. Interacts with and ubiquitinates ESR1; the interaction is promoted in the absence of estradiol (17-beta-estradiol/E2). Interacts with ESR2. Interacts with and ubiquitinates NFATC3; HSPA1A/HSP70 is required as a co-chaperone. In macrophages, interacts with PAQR3; the interaction promotes PPARG poylubiquitination and STUB1-mediated degradation. Component of the chaperone-assisted selective autophagy (CASA) complex consisting of BAG3, HSPA8/HSC70, HSPB8 and STUB1/CHIP.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion.

Tissue specificity. Expressed in differentiated myotubes (at protein level). Highly expressed in skeletal muscle, heart, pancreas, brain and placenta. Detected in kidney, liver and lung.

Post-translational modifications. Monoubiquitinated at Lys-2 following cell stress by UBE2W, promoting the interaction with ATXN3. Auto-ubiquitinated; mediated by UBE2D1 and UBE2D2 and enhanced in the presence of MAP2K5.

Disease relevance. Spinocerebellar ataxia, autosomal recessive, 16 (SCAR16) [MIM:615768] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR16 is characterized by truncal and limb ataxia resulting in gait instability. Additionally, patients may show dysarthria, nystagmus, spasticity of the lower limbs, and mild peripheral sensory neuropathy. The disease is caused by variants affecting the gene represented in this entry. Spinocerebellar ataxia 48 (SCA48) [MIM:618093] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA48 is an autosomal dominant neurodegenerative disease characterized by onset in mid-adulthood of progressive cognitive decline and gait ataxia, and vermian and hemispheric cerebellar atrophy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The U-box domain is required for the ubiquitin protein ligase activity. The TPR domain is essential for ubiquitination mediated by UBE2D1.

Induction. Up-regulated by inflammatory signals in regulatory T-cells (Treg).

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Antibodies against STUB1 are found in patients with chronic lymphocytic leukemia (CLL) and in colorectal cancer patients.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UNE7-1	1	yes
Q9UNE7-2	2

RefSeq proteins (2): NP_001280126, NP_005852* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003613	Ubox_domain	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR041312	CHIP_TPR_N	Domain
IPR045202	CHIP_RING-Ubox	Domain

Pfam: PF04564, PF12895, PF18391

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (47 total): sequence variant 13, helix 7, modified residue 5, region of interest 5, cross-link 4, repeat 3, mutagenesis site 3, sequence conflict 3, chain 1, compositionally biased region 1, splice variant 1, domain 1

Structure

Experimental structures (PDB)

27 structures.

PDB	Method	Resolution (Å)
9QFY	X-RAY DIFFRACTION	1.06
6NSV	X-RAY DIFFRACTION	1.3
9QFS	X-RAY DIFFRACTION	1.33
9QEU	X-RAY DIFFRACTION	1.35
8GCK	X-RAY DIFFRACTION	1.37
8EI0	X-RAY DIFFRACTION	1.47
6EFK	X-RAY DIFFRACTION	1.5
9QF1	X-RAY DIFFRACTION	1.51
8F16	X-RAY DIFFRACTION	1.56
9DYB	X-RAY DIFFRACTION	1.6
8SUV	X-RAY DIFFRACTION	1.63
8F14	X-RAY DIFFRACTION	1.69
8F15	X-RAY DIFFRACTION	1.73
7TB1	X-RAY DIFFRACTION	1.78
8FYU	X-RAY DIFFRACTION	1.85
9DYA	X-RAY DIFFRACTION	1.89
8EHZ	X-RAY DIFFRACTION	2.06
8F17	X-RAY DIFFRACTION	2.21
9R1P	X-RAY DIFFRACTION	2.29
4KBQ	X-RAY DIFFRACTION	2.91
9O7G	ELECTRON MICROSCOPY	3.1
9O7I	ELECTRON MICROSCOPY	3.4
9O7D	ELECTRON MICROSCOPY	3.6
9O7F	ELECTRON MICROSCOPY	3.7
9O7E	ELECTRON MICROSCOPY	3.9
9O7H	ELECTRON MICROSCOPY	4.8
9DRY	ELECTRON MICROSCOPY	7.02

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UNE7-F1	89.84	0.79

Antibody-complex structures (SAbDab): 1 — 9DRY

Functional residue map

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

Post-translational modifications (9): 19, 23, 25, 149, 273, 2, 22, 221, 255

Mutagenesis-validated functional residues (3):

Position	Phenotype
30	loss of interaction with foxp3 and its ability to ubiquitinate foxp3. loss of interaction with smad3, hspa8, hsp90aa1 an
260	loss of ability to ubiquitinate foxp3 and sirt6. abolishes stub1-mediated degradation of chrna3. abolishes autoubiquitin
269	abolishes e3 ligase activity.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-2173788	Downregulation of TGF-beta receptor signaling
R-HSA-5213460	RIPK1-mediated regulated necrosis
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-5675482	Regulation of necroptotic cell death
R-HSA-8863795	Downregulation of ERBB2 signaling
R-HSA-8939902	Regulation of RUNX2 expression and activity
R-HSA-8948751	Regulation of PTEN stability and activity
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 440 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, HORIUCHI_WTAP_TARGETS_DN, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_GLUCOCORTICOID_METABOLIC_PROCESS, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (37): MAPK cascade (GO:0000165), protein polyubiquitination (GO:0000209), response to ischemia (GO:0002931), DNA repair (GO:0006281), ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), protein quality control for misfolded or incompletely synthesized proteins (GO:0006515), negative regulation of cardiac muscle hypertrophy (GO:0010614), protein ubiquitination (GO:0016567), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), endoplasmic reticulum unfolded protein response (GO:0030968), positive regulation of protein ubiquitination (GO:0031398), regulation of protein stability (GO:0031647), regulation of glucocorticoid metabolic process (GO:0031943), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), negative regulation of smooth muscle cell apoptotic process (GO:0034392), positive regulation of smooth muscle cell apoptotic process (GO:0034393), cellular response to heat (GO:0034605), negative regulation of peroxisome proliferator activated receptor signaling pathway (GO:0035359), ERAD pathway (GO:0036503), ERBB2 signaling pathway (GO:0038128), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of proteolysis (GO:0045862), protein stabilization (GO:0050821), protein autoubiquitination (GO:0051865), chaperone-mediated autophagy (GO:0061684), protein K63-linked ubiquitination (GO:0070534), cellular response to misfolded protein (GO:0071218), cellular response to hypoxia (GO:0071456), positive regulation of chaperone-mediated protein complex assembly (GO:0090035), positive regulation of mitophagy (GO:1901526), positive regulation of ERAD pathway (GO:1904294), negative regulation of vascular associated smooth muscle contraction (GO:1904694), DNA damage response (GO:0006974), signal transduction (GO:0007165), positive regulation of metabolic process (GO:0009893), negative regulation of apoptotic process (GO:0043066)

GO Molecular Function (20): G protein-coupled receptor binding (GO:0001664), ubiquitin-protein transferase activity (GO:0004842), enzyme binding (GO:0019899), kinase binding (GO:0019900), Hsp70 protein binding (GO:0030544), protein-macromolecule adaptor activity (GO:0030674), TPR domain binding (GO:0030911), heat shock protein binding (GO:0031072), ubiquitin protein ligase binding (GO:0031625), ubiquitin-ubiquitin ligase activity (GO:0034450), protein homodimerization activity (GO:0042803), SMAD binding (GO:0046332), tau protein binding (GO:0048156), protein-folding chaperone binding (GO:0051087), misfolded protein binding (GO:0051787), Hsp90 protein binding (GO:0051879), ubiquitin protein ligase activity (GO:0061630), R-SMAD binding (GO:0070412), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (11): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), Z disc (GO:0030018), ubiquitin conjugating enzyme complex (GO:0031371), nuclear inclusion body (GO:0042405), protein folding chaperone complex (GO:0101031)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
TGF-beta receptor signaling activates SMADs	1
Regulated Necrosis	1
TNF signaling	1
RIPK1-mediated regulated necrosis	1
Signaling by ERBB2	1
Transcriptional regulation by RUNX2	1
PTEN Regulation	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	6
protein ubiquitination	4
cellular anatomical structure	4
intracellular protein-containing complex	3
intracellular membrane-bounded organelle	3
cytoplasm	3
response to endoplasmic reticulum stress	2
smooth muscle cell apoptotic process	2
regulation of smooth muscle cell apoptotic process	2
heat shock protein binding	2
transferase complex	2
intracellular signaling cassette	1
response to stress	1
DNA metabolic process	1
DNA damage response	1
modification-dependent protein catabolic process	1
protein catabolic process	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
negative regulation of muscle hypertrophy	1
protein modification by small protein conjugation	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
cellular response to unfolded protein	1
intracellular signal transduction	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
regulation of biological quality	1
glucocorticoid metabolic process	1
regulation of steroid metabolic process	1
regulation of hormone metabolic process	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
negative regulation of muscle cell apoptotic process	1
positive regulation of muscle cell apoptotic process	1
response to heat	1
cellular response to stress	1

Protein interactions and networks

STRING

4148 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STUB1	HSPA8	P11142	998
STUB1	HSPA4	P34932	998
STUB1	HSP90AA1	P07900	997
STUB1	HSP90AB1	P08238	997
STUB1	UBE2D1	P51668	992
STUB1	BAG3	O95817	991
STUB1	HSPB8	Q9UJY1	986
STUB1	BAG2	O95816	976
STUB1	DNAJB1	P25685	971
STUB1	UBE2N	P61088	943
STUB1	UBE4A	Q14139	926
STUB1	ATXN3	P54252	906
STUB1	HSPBP1	Q9NZL4	897
STUB1	RNF5	Q99942	891
STUB1	UBE4B	O95155	889

IntAct

576 interactions, top by confidence:

A	B	Type	Score
HSPA8	STUB1	psi-mi:“MI:0915”(physical association)	0.870
STUB1	HSPA8	psi-mi:“MI:0915”(physical association)	0.870
HSP90AA1	STUB1	psi-mi:“MI:0915”(physical association)	0.830
STUB1	HSP90AA1	psi-mi:“MI:0915”(physical association)	0.830
STUB1	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.780
HSPA1A	STUB1	psi-mi:“MI:0915”(physical association)	0.760
STUB1	HSPA1A	psi-mi:“MI:0915”(physical association)	0.760
STUB1	UBA1	psi-mi:“MI:0220”(ubiquitination reaction)	0.730
EGFR	STUB1	psi-mi:“MI:0915”(physical association)	0.720
OLFM3	STUB1	psi-mi:“MI:0915”(physical association)	0.670
STUB1	OLFM3	psi-mi:“MI:0915”(physical association)	0.670
STUB1	HSPB1	psi-mi:“MI:0915”(physical association)	0.670
FOXP3	STUB1	psi-mi:“MI:0915”(physical association)	0.640
FOXP3	STUB1	psi-mi:“MI:0914”(association)	0.640
FOXP3	STUB1	psi-mi:“MI:0403”(colocalization)	0.640
CPSF3	CPSF4	psi-mi:“MI:0914”(association)	0.640
ATCAY	STUB1	psi-mi:“MI:0915”(physical association)	0.630
STUB1	ATCAY	psi-mi:“MI:0915”(physical association)	0.630
STUB1	DAPK1	psi-mi:“MI:0407”(direct interaction)	0.590
STUB1	UBE2Q1	psi-mi:“MI:0915”(physical association)	0.580

BioGRID (1697): STUB1 (Affinity Capture-MS), STUB1 (Affinity Capture-Western), ERN1 (Reconstituted Complex), ERN1 (Biochemical Activity), UBE2N (Reconstituted Complex), HSPA8 (Biochemical Activity), STUB1 (Biochemical Activity), UBE2D3 (Reconstituted Complex), STUB1 (Affinity Capture-MS), STUB1 (Affinity Capture-Western), TP53 (Affinity Capture-Western), MAPT (Reconstituted Complex), HSPA8 (Reconstituted Complex), HSPA1B (Reconstituted Complex), HSP90AA1 (Reconstituted Complex)

ESM2 similar proteins: A0MT11, A1Z3X3, A4QNE0, A6HD62, D2XV59, F1N9S8, O00178, O08582, O43242, O60763, P14685, P41541, P41542, P50503, Q0JNK5, Q0P5I8, Q15006, Q28559, Q2KJ46, Q2R483, Q3TDN2, Q53PC7, Q58DC5, Q5BK32, Q5E993, Q5E9L7, Q5R4J9, Q5R882, Q5XGS8, Q5ZHY5, Q5ZLF0, Q6GLK9, Q6N069, Q6NRL4, Q6NYU2, Q6TGY8, Q75Q39, Q7L5D6, Q80UM3, Q8UUU2

Diamond homologs: A0AUS0, A2ZLU6, A6HD62, C6L7U1, D1FP53, E4NKF8, O81902, P0C6E7, Q058P4, Q0IMG9, Q0WUF6, Q10PI9, Q3E9F5, Q3E9F6, Q3E9F7, Q5FVN8, Q5PNY6, Q5UQ40, Q5VRH9, Q5ZHY5, Q5ZMC3, Q681N2, Q683D5, Q6EUK7, Q84TG3, Q8GUG9, Q8GUH1, Q8GWV5, Q8GZ84, Q8N9V3, Q8S8S7, Q8VZ40, Q91431, Q92021, Q94A51, Q9C7G1, Q9C7R6, Q9C8D1, Q9C9A6, Q9CAA7

SIGNOR signaling

48 interactions.

A	Effect	B	Mechanism
STUB1	down-regulates	SMAD1	ubiquitination
STUB1	down-regulates	SMAD5	ubiquitination
STUB1	“down-regulates quantity by destabilization”	HIF1A	ubiquitination
STUB1	“down-regulates quantity by destabilization”	CFTR	polyubiquitination
STUB1	“down-regulates quantity by destabilization”	SMG5	polyubiquitination
STUB1	“down-regulates quantity by destabilization”	CIP2A	polyubiquitination
STUB1	“down-regulates quantity by destabilization”	SMAD4	polyubiquitination
STUB1	“down-regulates quantity by destabilization”	SMAD1	polyubiquitination
STUB1	“down-regulates quantity by destabilization”	NRK	polyubiquitination
STUB1	“down-regulates quantity by destabilization”	CD274	destabilization
STUB1	“down-regulates quantity by destabilization”	CBX4	ubiquitination
STUB1	“down-regulates quantity by destabilization”	IRS4	polyubiquitination
STUB1	“down-regulates quantity by destabilization”	PLK1	ubiquitination
STUB1	“down-regulates quantity by destabilization”	SNAI1	ubiquitination
STUB1	“down-regulates quantity by destabilization”	POU5F1	ubiquitination
STUB1	“down-regulates quantity by destabilization”	FMR1	ubiquitination
STUB1	“down-regulates quantity by destabilization”	RUNX2	ubiquitination
STUB1	“down-regulates quantity by destabilization”	LRRK2	ubiquitination
STUB1	“down-regulates quantity by destabilization”	ERBB2	ubiquitination
STUB1	“up-regulates activity”	INO80	ubiquitination
STUB1	“down-regulates quantity by destabilization”	ATXN1	ubiquitination
STUB1	“down-regulates quantity by destabilization”	ATXN3	ubiquitination
STUB1	“down-regulates quantity by destabilization”	CFTR	ubiquitination
STUB1	“down-regulates quantity by destabilization”	EIF4E	ubiquitination
STUB1	“down-regulates quantity by destabilization”	TRAF6	ubiquitination
STUB1	“down-regulates quantity”	BACE1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 140 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
Attenuation phase	5	19.6×	6e-04
HSF1-dependent transactivation	6	18.3×	1e-04
PINK1-PRKN Mediated Mitophagy	5	17.2×	8e-04
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	7	13.0×	1e-04
Oncogenic MAPK signaling	5	11.9×	3e-03
Aggrephagy	5	11.9×	3e-03
Regulation of HSF1-mediated heat shock response	8	10.7×	1e-04
Post NMDA receptor activation events	5	9.8×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein refolding	5	25.2×	1e-03
cellular response to heat	6	16.6×	1e-03
regulation of autophagy	6	11.7×	3e-03
positive regulation of protein localization to plasma membrane	5	11.0×	9e-03
protein import into nucleus	7	8.1×	3e-03
protein folding	8	6.7×	3e-03
protein stabilization	10	5.4×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	12
Uncertain significance	61
Likely benign	31
Benign	7

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1027426	NM_005861.4(STUB1):c.199G>A (p.Ala67Thr)	Pathogenic
127143	NM_005861.4(STUB1):c.493C>T (p.Leu165Phe)	Pathogenic
127144	NM_005861.4(STUB1):c.389A>T (p.Asn130Ile)	Pathogenic
127145	NM_005861.4(STUB1):c.441G>T (p.Trp147Cys)	Pathogenic
127149	NM_005861.4(STUB1):c.235G>A (p.Ala79Thr)	Pathogenic
1701267	NM_005861.4(STUB1):c.440G>A (p.Trp147Ter)	Pathogenic
2584742	NM_005861.4(STUB1):c.168C>G (p.Asn56Lys)	Pathogenic
3067686	NM_005861.4(STUB1):c.384_387dup (p.Asn130fs)	Pathogenic
623185	NM_005861.4(STUB1):c.885dup (p.Glu296Ter)	Pathogenic
986942	NM_005861.4(STUB1):c.65del (p.Lys22fs)	Pathogenic
997699	NM_005861.4(STUB1):c.97G>A (p.Gly33Ser)	Pathogenic
997700	NM_005861.4(STUB1):c.682C>T (p.Pro228Ser)	Pathogenic
1027454	NM_005861.4(STUB1):c.170C>T (p.Pro57Leu)	Likely pathogenic
127150	NM_005861.4(STUB1):c.236C>A (p.Ala79Asp)	Likely pathogenic
162097	NM_005861.4(STUB1):c.194A>G (p.Asn65Ser)	Likely pathogenic
1679956	NM_005861.4(STUB1):c.778dup (p.His260fs)	Likely pathogenic
1687153	NM_005861.4(STUB1):c.469C>T (p.Gln157Ter)	Likely pathogenic
1698848	NM_005861.4(STUB1):c.525-1G>A	Likely pathogenic
2503107	NM_005861.4(STUB1):c.207C>G (p.Cys69Trp)	Likely pathogenic
3377516	NM_005861.4(STUB1):c.3G>T (p.Met1Ile)	Likely pathogenic
4280814	NM_005861.4(STUB1):c.393C>A (p.Phe131Leu)	Likely pathogenic
4532287	NM_005861.4(STUB1):c.159+1G>C	Likely pathogenic
807331	NM_005861.4(STUB1):c.518del (p.Arg173fs)	Likely pathogenic
982033	NM_005861.4(STUB1):c.760C>G (p.Arg254Gly)	Likely pathogenic

SpliceAI

1032 predictions. Top by Δscore:

Variant	Effect	Δscore
16:680681:GATC:G	donor_gain	1.0000
16:680685:G:GG	donor_gain	1.0000
16:681319:C:G	donor_gain	1.0000
16:681346:GCGAG:G	donor_gain	1.0000
16:681347:CGAGG:C	donor_loss	1.0000
16:681348:GAGG:G	donor_loss	1.0000
16:681349:AGGTT:A	donor_loss	1.0000
16:681350:GGT:G	donor_loss	1.0000
16:681435:CAGCT:C	acceptor_loss	1.0000
16:681436:A:AG	acceptor_gain	1.0000
16:681437:G:GA	acceptor_gain	1.0000
16:681437:GCTT:G	acceptor_gain	1.0000
16:681551:G:GT	donor_gain	1.0000
16:681552:A:T	donor_gain	1.0000
16:681595:GC:G	donor_gain	1.0000
16:681600:AGAGG:A	donor_loss	1.0000
16:681602:AGGTG:A	donor_loss	1.0000
16:681604:GT:G	donor_loss	1.0000
16:681605:T:A	donor_loss	1.0000
16:681698:G:GT	donor_gain	1.0000
16:681699:A:T	donor_gain	1.0000
16:681708:G:T	donor_gain	1.0000
16:681877:GCAC:G	donor_gain	1.0000
16:681881:G:GG	donor_gain	1.0000
16:682072:GGAAG:G	donor_gain	1.0000
16:682073:GAAGG:G	donor_gain	1.0000
16:682074:AAGGT:A	donor_loss	1.0000
16:682075:AGGTG:A	donor_loss	1.0000
16:682076:GGTG:G	donor_loss	1.0000
16:682077:GTGA:G	donor_loss	1.0000

AlphaMissense

2008 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:680615:G:C	K30N	1.000
16:680615:G:T	K30N	1.000
16:680622:G:C	G33R	1.000
16:680623:G:A	G33D	1.000
16:680623:G:T	G33V	1.000
16:681189:G:C	R66P	1.000
16:681191:G:C	A67P	1.000
16:681192:C:A	A67D	1.000
16:681197:T:C	C69R	1.000
16:681198:G:A	C69Y	1.000
16:681199:C:G	C69W	1.000
16:681241:C:G	C83W	1.000
16:681277:G:C	K95N	1.000
16:681277:G:T	K95N	1.000
16:681293:G:A	G101R	1.000
16:681293:G:C	G101R	1.000
16:681293:G:T	G101W	1.000
16:681294:G:A	G101E	1.000
16:681342:T:C	L117P	1.000
16:681450:C:A	A124D	1.000
16:681470:T:C	F131L	1.000
16:681472:C:A	F131L	1.000
16:681472:C:G	F131L	1.000
16:681474:G:A	G132E	1.000
16:682187:T:C	L231P	1.000
16:682192:G:C	G233R	1.000
16:682199:T:A	I235N	1.000
16:682199:T:C	I235T	1.000
16:682199:T:G	I235S	1.000
16:682201:A:C	S236R	1.000

dbSNP variants (sampled 300 via entrez): RS1000069116 (16:679453 C>G), RS1000603813 (16:682627 C>A,G,T), RS1000849558 (16:679278 G>C), RS1001417861 (16:679536 C>G,T), RS1001785357 (16:679783 C>T), RS1002292101 (16:680281 C>G,T), RS1002391688 (16:678756 G>A), RS1002406618 (16:680421 G>A,C), RS1002766959 (16:679001 C>T), RS1002829648 (16:678503 G>A,T), RS1003485847 (16:682162 C>T), RS1003852324 (16:681490 C>T), RS1004703683 (16:682553 T>A), RS1005719910 (16:681550 G>A), RS1005748540 (16:681723 G>A,C)

Disease associations

OMIM: gene MIM:607207 | disease phenotypes: MIM:618093, MIM:615768

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive spinocerebellar ataxia 16	Strong	Autosomal recessive
spinocerebellar ataxia 48	Strong	Autosomal dominant

Mondo (2): spinocerebellar ataxia 48 (MONDO:0032526), autosomal recessive spinocerebellar ataxia 16 (MONDO:0014339)

Orphanet (2): Spinocerebellar ataxia type 48 (Orphanet:631103), Autosomal recessive cerebellar ataxia due to STUB1 deficiency (Orphanet:412057)

HPO phenotypes

76 total (30 of 76 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000135	Hypogonadism
HP:0000365	Hearing impairment
HP:0000501	Glaucoma
HP:0000544	External ophthalmoplegia
HP:0000602	Ophthalmoplegia
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000657	Oculomotor apraxia
HP:0000666	Horizontal nystagmus
HP:0000716	Depression
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000789	Infertility
HP:0000821	Hypothyroidism
HP:0000876	Oligomenorrhea
HP:0001094	Iridocyclitis
HP:0001105	Retinal atrophy
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001166	Arachnodactyly
HP:0001181	Adducted thumb
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST010796_5294	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-09
GCST010796_5295	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08
GCST010796_5296	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_5297	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465258 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — E3 ubiquitin ligase components

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
peptide 22d	Binding	6.28	pKd

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.00	IC50	1000	nM	CHEMBL5561795
5.60	IC50	2500	nM	CHEMBL5558181
5.60	IC50	2500	nM	CHEMBL5558644

PubChem BioAssay actives

3 with measured affinity, of 23 total; 3 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
N,N’-bis(3-carbamoyl-6-ethyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pentanediamide	2084025: Inhibition of GST-tagged human CHIP expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	ic50	1.0000	uM
N,N’-bis(3-carbamoyl-4,5-dimethylthiophen-2-yl)pentanediamide	2084025: Inhibition of GST-tagged human CHIP expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	ic50	2.5000	uM
methyl 2-[[2-[[5,6-bis(furan-2-yl)-1,2,4-triazin-3-yl]sulfanyl]acetyl]amino]-4,5-dimethylthiophene-3-carboxylate	2084025: Inhibition of GST-tagged human CHIP expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	ic50	2.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	4
geldanamycin	affects binding, decreases reaction, increases reaction, increases degradation	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
afimoxifene	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
solanesol	affects binding, decreases reaction, increases reaction	1
sodium arsenite	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
4-aminophenylarsenoxide	decreases reaction, affects binding	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	decreases expression	1
2-phenylacetylenesulfonamide	affects binding, decreases reaction, increases reaction	1
3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone	affects reaction, increases expression	1
N2-(1H-indazole-5-yl)-N6-methyl-3-nitropyridine-2,6-diamine	affects binding, decreases reaction, increases reaction	1
bisphenol AF	increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Fulvestrant	affects binding, decreases reaction	1
Vorinostat	increases degradation, increases reaction	1
Air Pollutants, Occupational	affects expression	1
Benzo(a)pyrene	increases methylation	1
Benztropine	affects cotreatment, decreases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Curcumin	decreases expression	1
Diazinon	increases methylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	affects binding, decreases reaction	1
Ivermectin	decreases expression	1
Manganese	decreases expression, increases abundance	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5317334	Binding	Inhibition of N-terminal Flag-tagged full-length U-box E3 CHIP (unknown origin) self-ubiquitination expressed in Escherichia coli BL21 (DE3) cells assessed as inhibition of Uba1-UbcH5B-CHIP cascade at upto 50 uM preincubated for 30 mins fol	Inhibition of the Ubiquitin Transfer Cascade by a Peptidomimetic Foldamer Mimicking the E2 N-Terminal Helix. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9TG	Ubigene HEK293 STUB1 KO	Transformed cell line	Female
CVCL_UL60	HIHCNi004-A-1	Induced pluripotent stem cell	Female
CVCL_VG85	HIHCNi001-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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