Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1PVAZA)

DOT Name E3 ubiquitin-protein ligase HECW1 (HECW1)
Synonyms EC 2.3.2.26; HECT, C2 and WW domain-containing protein 1; HECT-type E3 ubiquitin transferase HECW1; NEDD4-like E3 ubiquitin-protein ligase 1; hNEDL1
Gene Name HECW1
Related Disease
Alzheimer disease ( )
Breast cancer ( )
Breast carcinoma ( )
IgA nephropathy ( )
Osteoarthritis ( )
Acute myelogenous leukaemia ( )
Autoimmune disease ( )
Emery-Dreifuss muscular dystrophy ( )
UniProt ID
HECW1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
3L4H
EC Number
2.3.2.26
Pfam ID
PF00168 ; PF00632 ; PF18436 ; PF16562 ; PF00397
Sequence
MLLHLCSVKNLYQNRFLGLAAMASPSRNSQSRRRCKEPLRYSYNPDQFHNMDLRGGPHDG
VTIPRSTSDTDLVTSDSRSTLMVSSSYYSIGHSQDLVIHWDIKEEVDAGDWIGMYLIDEV
LSENFLDYKNRGVNGSHRGQIIWKIDASSYFVEPETKICFKYYHGVSGALRATTPSVTVK
NSAAPIFKSIGADETVQGQGSRRLISFSLSDFQAMGLKKGMFFNPDPYLKISIQPGKHSI
FPALPHHGQERRSKIIGNTVNPIWQAEQFSFVSLPTDVLEIEVKDKFAKSRPIIKRFLGK
LSMPVQRLLERHAIGDRVVSYTLGRRLPTDHVSGQLQFRFEITSSIHPDDEEISLSTEPE
SAQIQDSPMNNLMESGSGEPRSEAPESSESWKPEQLGEGSVPDGPGNQSIELSRPAEEAA
VITEAGDQGMVSVGPEGAGELLAQVQKDIQPAPSAEELAEQLDLGEEASALLLEDGEAPA
STKEEPLEEEATTQSRAGREEEEKEQEEEGDVSTLEQGEGRLQLRASVKRKSRPCSLPVS
ELETVIASACGDPETPRTHYIRIHTLLHSMPSAQGGSAAEEEDGAEEESTLKDSSEKDGL
SEVDTVAADPSALEEDREEPEGATPGTAHPGHSGGHFPSLANGAAQDGDTHPSTGSESDS
SPRQGGDHSCEGCDASCCSPSCYSSSCYSTSCYSSSCYSASCYSPSCYNGNRFASHTRFS
SVDSAKISESTVFSSQDDEEEENSAFESVPDSMQSPELDPESTNGAGPWQDELAAPSGHV
ERSPEGLESPVAGPSNRREGECPILHNSQPVSQLPSLRPEHHHYPTIDEPLPPNWEARID
SHGRVFYVDHVNRTTTWQRPTAAATPDGMRRSGSIQQMEQLNRRYQNIQRTIATERSEED
SGSQSCEQAPAGGGGGGGSDSEAESSQSSLDLRREGSLSPVNSQKITLLLQSPAVKFITN
PEFFTVLHANYSAYRVFTSSTCLKHMILKVRRDARNFERYQHNRDLVNFINMFADTRLEL
PRGWEIKTDQQGKSFFVDHNSRATTFIDPRIPLQNGRLPNHLTHRQHLQRLRSYSAGEAS
EVSRNRGASLLARPGHSLVAAIRSQHQHESLPLAYNDKIVAFLRQPNIFEMLQERQPSLA
RNHTLREKIHYIRTEGNHGLEKLSCDADLVILLSLFEEEIMSYVPLQAAFHPGYSFSPRC
SPCSSPQNSPGLQRASARAPSPYRRDFEAKLRNFYRKLEAKGFGQGPGKIKLIIRRDHLL
EGTFNQVMAYSRKELQRNKLYVTFVGEEGLDYSGPSREFFFLLSQELFNPYYGLFEYSAN
DTYTVQISPMSAFVENHLEWFRFSGRILGLALIHQYLLDAFFTRPFYKALLRLPCDLSDL
EYLDEEFHQSLQWMKDNNITDILDLTFTVNEEVFGQVTERELKSGGANTQVTEKNKKEYI
ERMVKWRVERGVVQQTEALVRGFYEVVDSRLVSVFDARELELVIAGTAEIDLNDWRNNTE
YRGGYHDGHLVIRWFWAAVERFNNEQRLRLLQFVTGTSSVPYEGFAALRGSNGLRRFCIE
KWGKITSLPRAHTCFNRLDLPPYPSYSMLYEKLLTAVEETSTFGLE
Function
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent degradation of DVL1. Also targets the mutant SOD1 protein involved in familial amyotrophic lateral sclerosis (FALS). Forms cytotoxic aggregates with DVL1, SSR3 and mutant SOD1 that lead to motor neuron death in FALS.
Tissue Specificity Predominantly expressed in neurons of adult and fetal brain. Weakly expressed in the kidney.
Reactome Pathway
Degradation of DVL (R-HSA-4641258 )

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Alzheimer disease DISF8S70 Strong Genetic Variation [1]
Breast cancer DIS7DPX1 Strong Biomarker [2]
Breast carcinoma DIS2UE88 Strong Biomarker [2]
IgA nephropathy DISZ8MTK Strong Altered Expression [3]
Osteoarthritis DIS05URM Strong Genetic Variation [4]
Acute myelogenous leukaemia DISCSPTN moderate Genetic Variation [5]
Autoimmune disease DISORMTM moderate Biomarker [6]
Emery-Dreifuss muscular dystrophy DISYTPR5 Limited Altered Expression [7]
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⏷ Show the Full List of 8 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
3 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the methylation of E3 ubiquitin-protein ligase HECW1 (HECW1). [8]
Arsenic DMTL2Y1 Approved Arsenic affects the methylation of E3 ubiquitin-protein ligase HECW1 (HECW1). [9]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase HECW1 (HECW1). [11]
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2 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the mutagenesis of E3 ubiquitin-protein ligase HECW1 (HECW1). [10]
Sulforaphane DMQY3L0 Investigative Sulforaphane increases the expression of E3 ubiquitin-protein ligase HECW1 (HECW1). [12]
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References

1 Genome-wide association study of the rate of cognitive decline in Alzheimer's disease.Alzheimers Dement. 2014 Jan;10(1):45-52. doi: 10.1016/j.jalz.2013.01.008. Epub 2013 Mar 25.
2 Overexpression of WWP1 is associated with the estrogen receptor and insulin-like growth factor receptor 1 in breast carcinoma.Int J Cancer. 2009 Jun 15;124(12):2829-36. doi: 10.1002/ijc.24266.
3 Changes E3 ubiquitin protein ligase 1 gene mRNA expression correlated with IgA1 glycosylation in patients with IgA nephropathy.Ren Fail. 2019 Nov;41(1):370-376. doi: 10.1080/0886022X.2019.1605295.
4 Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis.Nat Genet. 2018 Apr;50(4):549-558. doi: 10.1038/s41588-018-0079-y. Epub 2018 Mar 20.
5 Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
6 Regulation of autoimmune disease by the E3 ubiquitin ligase Itch.Cell Immunol. 2019 Jun;340:103916. doi: 10.1016/j.cellimm.2019.04.004. Epub 2019 Apr 5.
7 E3 ubiquitin ligase HECW2 targets PCNA and lamin B1.Biochim Biophys Acta Mol Cell Res. 2018 Aug;1865(8):1088-1104. doi: 10.1016/j.bbamcr.2018.05.008. Epub 2018 May 17.
8 Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
9 Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
10 Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
11 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
12 Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.