Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRGGM2Z)

• DOT Name: Alpha- and gamma-adaptin-binding protein p34 (AAGAB)
• Gene Name: AAGAB
• Related Disease:
  Ataxia-telangiectasia
  Cardiovascular disease
  Familial adenomatous polyposis
  Mal de Meleda
  Palmoplantar keratoderma, punctate type 1A
  Punctate palmoplantar keratoderma type 1
  Skin disease
  Xeroderma pigmentosum
• UniProt ID: AAGAB_HUMAN
• PDB ID: 7TWD
• Pfam ID: PF10199
• Sequence:
  MAAGVPCALVTSCSSVFSGDQLVQHILGTEDLIVEVTSNDAVRFYPWTIDNKYYSADINL
  CVVPNKFLVTAEIAESVQAFVVYFDSTQKSGLDSVSSWLPLAKAWLPEVMILVCDRVSED
  GINRQKAQEWCIKHGFELVELSPEELPEEDDDFPESTGVKRIVQALNANVWSNVVMKNDR
  NQGFSLLNSLTGTNHSIGSADPCHPEQPHLPAADSTESLSDHRGGASNTTDAQVDSIVDP
  MLDLDIQELASLTTGGGDVENFERLFSKLKEMKDKAATLPHEQRKVHAEKVAKAFWMAIG
  GDRDEIEGLSSDEEH
• Function: May be involved in endocytic recycling of growth factor receptors such as EGFR.
• Tissue Specificity: Widely expressed, including in skin and keratinocytes, with highest levels in adrenal gland, rectum and thymus.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[1]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[2]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[3]
Mal de Meleda	DISVLL9A	Strong	Biomarker	[4]
Palmoplantar keratoderma, punctate type 1A	DISCGAJS	Strong	Autosomal dominant	[5]
Punctate palmoplantar keratoderma type 1	DISFZKWR	Supportive	Autosomal dominant	[6]
Skin disease	DISDW8R6	Limited	Genetic Variation	[7]
Xeroderma pigmentosum	DISQ9H19	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Alpha- and gamma-adaptin-binding protein p34 (AAGAB).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alpha- and gamma-adaptin-binding protein p34 (AAGAB).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Alpha- and gamma-adaptin-binding protein p34 (AAGAB).	[13]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Alpha- and gamma-adaptin-binding protein p34 (AAGAB).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Alpha- and gamma-adaptin-binding protein p34 (AAGAB).	[12]

References

• [1] Ionizing radiation-induced phosphorylation of RPA p34 is deficient in ataxia telangiectasia and reduced in aged normal fibroblasts.Radiother Oncol. 1996 Apr;39(1):43-52. doi: 10.1016/0167-8140(96)01712-4.
• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] Phosphorylation of the tumor suppressor adenomatous polyposis coli (APC) by the cyclin-dependent kinase p34.J Biol Chem. 1997 Aug 29;272(35):21681-4. doi: 10.1074/jbc.272.35.21681.
• [4] Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma.Nat Genet. 2012 Nov;44(11):1272-6. doi: 10.1038/ng.2444. Epub 2012 Oct 14.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type Buschke-Fischer-Brauer. Am J Hum Genet. 2012 Oct 5;91(4):754-9. doi: 10.1016/j.ajhg.2012.08.024. Epub 2012 Sep 20.
• [7] Clathrin Adaptor Complex-interacting Protein Irc6 Functions through the Conserved C-Terminal Domain.Sci Rep. 2019 Mar 14;9(1):4436. doi: 10.1038/s41598-019-40852-8.
• [8] The intricate network between the p34 and p44 subunits is central to the activity of the transcription/DNA repair factor TFIIH.Nucleic Acids Res. 2017 Oct 13;45(18):10872-10883. doi: 10.1093/nar/gkx743.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] 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.
• [12] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.