Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD1UGUN)

• DOT Name: AP-2 complex subunit alpha-2 (AP2A2)
• Synonyms: 100 kDa coated vesicle protein C; Adaptor protein complex AP-2 subunit alpha-2; Adaptor-related protein complex 2 subunit alpha-2; Alpha-adaptin C; Alpha2-adaptin; Clathrin assembly protein complex 2 alpha-C large chain; Huntingtin yeast partner J; Huntingtin-interacting protein 9; HIP-9; Huntingtin-interacting protein J; Plasma membrane adaptor HA2/AP2 adaptin alpha C subunit
• Gene Name: AP2A2
• Related Disease:
  Coronary atherosclerosis
  Coronary heart disease
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Progressive supranuclear palsy
  Chronic bronchitis
  Asthma
  Schizophrenia
• UniProt ID: AP2A2_HUMAN
• Pfam ID: PF01602 ; PF02296 ; PF02883
• Sequence:
  MPAVSKGDGMRGLAVFISDIRNCKSKEAEIKRINKELANIRSKFKGDKALDGYSKKKYVC
  KLLFIFLLGHDIDFGHMEAVNLLSSNRYTEKQIGYLFISVLVNSNSELIRLINNAIKNDL
  ASRNPTFMGLALHCIASVGSREMAEAFAGEIPKVLVAGDTMDSVKQSAALCLLRLYRTSP
  DLVPMGDWTSRVVHLLNDQHLGVVTAATSLITTLAQKNPEEFKTSVSLAVSRLSRIVTSA
  STDLQDYTYYFVPAPWLSVKLLRLLQCYPPPDPAVRGRLTECLETILNKAQEPPKSKKVQ
  HSNAKNAVLFEAISLIIHHDSEPNLLVRACNQLGQFLQHRETNLRYLALESMCTLASSEF
  SHEAVKTHIETVINALKTERDVSVRQRAVDLLYAMCDRSNAPQIVAEMLSYLETADYSIR
  EEIVLKVAILAEKYAVDYTWYVDTILNLIRIAGDYVSEEVWYRVIQIVINRDDVQGYAAK
  TVFEALQAPACHENLVKVGGYILGEFGNLIAGDPRSSPLIQFHLLHSKFHLCSVPTRALL
  LSTYIKFVNLFPEVKPTIQDVLRSDSQLRNADVELQQRAVEYLRLSTVASTDILATVLEE
  MPPFPERESSILAKLKKKKGPSTVTDLEDTKRDRSVDVNGGPEPAPASTSAVSTPSPSAD
  LLGLGAAPPAPAGPPPSSGGSGLLVDVFSDSASVVAPLAPGSEDNFARFVCKNNGVLFEN
  QLLQIGLKSEFRQNLGRMFIFYGNKTSTQFLNFTPTLICSDDLQPNLNLQTKPVDPTVEG
  GAQVQQVVNIECVSDFTEAPVLNIQFRYGGTFQNVSVQLPITLNKFFQPTEMASQDFFQR
  WKQLSNPQQEVQNIFKAKHPMDTEVTKAKIIGFGSALLEEVDPNPANFVGAGIIHTKTTQ
  IGCLLRLEPNLQAQMYRLTLRTSKEAVSQRLCELLSAQF
• Function: Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. During long-term potentiation in hippocampal neurons, AP-2 is responsible for the endocytosis of ADAM10. The AP-2 alpha subunit binds polyphosphoinositide-containing lipids, positioning AP-2 on the membrane. The AP-2 alpha subunit acts via its C-terminal appendage domain as a scaffolding platform for endocytic accessory proteins. The AP-2 alpha and AP-2 sigma subunits are thought to contribute to the recognition of the [ED]-X-X-X-L-[LI] motif.
• Tissue Specificity: Expressed in the brain (at protein level).
• KEGG Pathway:
  Endocytosis (hsa04144)
  Sy.ptic vesicle cycle (hsa04721)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Huntington disease (hsa05016)
• Reactome Pathway:
  Retrograde neurotrophin signalling (R-HSA-177504)
  Nef Mediated CD8 Down-regulation (R-HSA-182218)
  MHC class II antigen presentation (R-HSA-2132295)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  Recycling pathway of L1 (R-HSA-437239)
  WNT5A-dependent internalization of FZD4 (R-HSA-5099900)
  WNT5A-dependent internalization of FZD2, FZD5 and ROR2 (R-HSA-5140745)
  Neutrophil degranulation (R-HSA-6798695)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  VLDLR internalisation and degradation (R-HSA-8866427)
  LDL clearance (R-HSA-8964038)
  Potential therapeutics for SARS (R-HSA-9679191)
  Nef Mediated CD4 Down-regulation (R-HSA-167590)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary atherosclerosis	DISKNDYU	Definitive	Genetic Variation	[1]
Coronary heart disease	DIS5OIP1	Definitive	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Progressive supranuclear palsy	DISO5KRQ	Strong	Biomarker	[3]
Chronic bronchitis	DISS8O8V	moderate	Genetic Variation	[4]
Asthma	DISW9QNS	Limited	Genetic Variation	[5]
Schizophrenia	DISSRV2N	Limited	Unknown	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ritonavir	DMU764S	Approved	AP-2 complex subunit alpha-2 (AP2A2) increases the Insulin resistance ADR of Ritonavir.	[17]

4 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 AP-2 complex subunit alpha-2 (AP2A2).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of AP-2 complex subunit alpha-2 (AP2A2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of AP-2 complex subunit alpha-2 (AP2A2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of AP-2 complex subunit alpha-2 (AP2A2).	[16]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of AP-2 complex subunit alpha-2 (AP2A2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AP-2 complex subunit alpha-2 (AP2A2).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of AP-2 complex subunit alpha-2 (AP2A2).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of AP-2 complex subunit alpha-2 (AP2A2).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of AP-2 complex subunit alpha-2 (AP2A2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of AP-2 complex subunit alpha-2 (AP2A2).	[14]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of AP-2 complex subunit alpha-2 (AP2A2).	[15]

References

• [1] A genetic variant near adaptor-related protein complex 2 alpha 2 subunit gene is associated with coronary artery disease in a Chinese population.BMC Cardiovasc Disord. 2018 Aug 7;18(1):161. doi: 10.1186/s12872-018-0905-2.
• [2] New Gene Profiling in Determination of Breast Cancer Recurrence and Prognosis in Iranian Women.Asian Pac J Cancer Prev. 2016;17(S3):155-60. doi: 10.7314/apjcp.2016.17.s3.155.
• [3] Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene.J Neuropathol Exp Neurol. 2020 Jan 1;79(1):3-21. doi: 10.1093/jnen/nlz116.
• [4] Genetic susceptibility for chronic bronchitis in chronic obstructive pulmonary disease.Respir Res. 2014 Sep 21;15(1):113. doi: 10.1186/s12931-014-0113-2.
• [5] Identification of Four Novel Loci in Asthma in European American and African American Populations.Am J Respir Crit Care Med. 2017 Feb 15;195(4):456-463. doi: 10.1164/rccm.201604-0861OC.
• [6] De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat Genet. 2012 Dec;44(12):1365-9. doi: 10.1038/ng.2446. Epub 2012 Oct 3.
• [7] 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.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] 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.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [15] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [16] 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.
• [17] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.