Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE3EXWZ)

• DOT Name: Clathrin coat assembly protein AP180 (SNAP91)
• Synonyms: 91 kDa synaptosomal-associated protein; Clathrin coat-associated protein AP180; Phosphoprotein F1-20
• Gene Name: SNAP91
• Related Disease:
  Essential tremor
  T-cell acute lymphoblastic leukaemia
  Acute leukaemia
  Acute megakaryoblastic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  Amyloidosis
  Anxiety
  Anxiety disorder
  Arrhythmia
  Catecholaminergic polymorphic ventricular tachycardia 1
  Chromosomal disorder
  Cleft lip/palate
  Deafness
  Glioblastoma multiforme
  Glioma
  Haematological malignancy
  Long QT syndrome
  Lymphoma
  Monocytic leukemia
  Myeloid leukaemia
  Paroxysmal familial ventricular fibrillation
  Legius syndrome
  leukaemia
  Neurofibromatosis type 1
  Acute lymphocytic leukaemia
  Childhood acute lymphoblastic leukemia
  Leukemia
  Schizophrenia
• UniProt ID: AP180_HUMAN
• Pfam ID: PF07651
• Sequence:
  MSGQTLTDRIAAAQYSVTGSAVARAVCKATTHEVMGPKKKHLDYLIQATNETNVNIPQMA
  DTLFERATNSSWVVVFKALVTTHHLMVHGNERFIQYLASRNTLFNLSNFLDKSGSHGYDM
  STFIRRYSRYLNEKAFSYRQMAFDFARVKKGADGVMRTMAPEKLLKSMPILQGQIDALLE
  FDVHPNELTNGVINAAFMLLFKDLIKLFACYNDGVINLLEKFFEMKKGQCKDALEIYKRF
  LTRMTRVSEFLKVAEQVGIDKGDIPDLTQAPSSLMETLEQHLNTLEGKKPGNNEGSGAPS
  PLSKSSPATTVTSPNSTPAKTIDTSPPVDLFATASAAVPVSTSKPSSDLLDLQPDFSSGG
  AAAAAAPAPPPPAGGATAWGDLLGEDSLAALSSVPSEAQISDPFAPEPTPPTTTAEIATA
  SASASTTTTVTAVTAEVDLFGDAFAASPGEAPAASEGAAAPATPTPVAAALDACSGNDPF
  APSEGSAEAAPELDLFAMKPPETSVPVVTPTASTAPPVPATAPSPAPAVAAAAAATTAAT
  AAATTTTTTSAATATTAPPALDIFGDLFESTPEVAAAPKPDAAPSIDLFSTDAFSSPPQG
  ASPVPESSLTADLLSVDAFAAPSPATTASPAKVDSSGVIDLFGDAFGSSASEPQPASQAA
  SSSSASADLLAGFGGSFMAPSPSPVTPAQNNLLQPNFEAAFGTTPSTSSSSSFDPSVFDG
  LGDLLMPTMAPAGQPAPVSMVPPSPAMAASKALGSDLDSSLASLVGNLGISGTTTKKGDL
  QWNAGEKKLTGGANWQPKVAPATWSAGVPPSAPLQGAVPPTSSVPPVAGAPSVGQPGAGF
  GMPPAGTGMPMMPQQPVMFAQPMMRPPFGAAAVPGTQLSPSPTPASQSPKKPPAKDPLAD
  LNIKDFL
• Function: Adaptins are components of the adapter complexes which link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. Binding of AP180 to clathrin triskelia induces their assembly into 60-70 nm coats.
• Reactome Pathway:
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Essential tremor	DIS7GBKQ	Definitive	Biomarker	[1]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Biomarker	[2]
Acute leukaemia	DISDQFDI	Strong	Biomarker	[3]
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Altered Expression	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Alzheimer disease	DISF8S70	Strong	Biomarker	[7]
Amyloidosis	DISHTAI2	Strong	Biomarker	[8]
Anxiety	DISIJDBA	Strong	Biomarker	[9]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[10]
Arrhythmia	DISFF2NI	Strong	Biomarker	[11]
Catecholaminergic polymorphic ventricular tachycardia 1	DISKGB3F	Strong	Genetic Variation	[11]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[12]
Cleft lip/palate	DIS14IG3	Strong	Biomarker	[13]
Deafness	DISKCLH4	Strong	Genetic Variation	[14]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[15]
Glioma	DIS5RPEH	Strong	Altered Expression	[15]
Haematological malignancy	DISCDP7W	Strong	Biomarker	[16]
Long QT syndrome	DISMKWS3	Strong	Genetic Variation	[11]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[17]
Monocytic leukemia	DIS8M755	Strong	Genetic Variation	[18]
Myeloid leukaemia	DISMN944	Strong	Genetic Variation	[19]
Paroxysmal familial ventricular fibrillation	DISRM7IX	Strong	Biomarker	[11]
Legius syndrome	DISO9AOZ	moderate	Biomarker	[20]
leukaemia	DISS7D1V	moderate	Biomarker	[21]
Neurofibromatosis type 1	DIS53JH9	moderate	Biomarker	[20]
Acute lymphocytic leukaemia	DISPX75S	Limited	Biomarker	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Genetic Variation	[17]
Leukemia	DISNAKFL	Limited	Biomarker	[22]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[23]

9 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 Clathrin coat assembly protein AP180 (SNAP91).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Clathrin coat assembly protein AP180 (SNAP91).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Clathrin coat assembly protein AP180 (SNAP91).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Clathrin coat assembly protein AP180 (SNAP91).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Clathrin coat assembly protein AP180 (SNAP91).	[28]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Clathrin coat assembly protein AP180 (SNAP91).	[29]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Clathrin coat assembly protein AP180 (SNAP91).	[30]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Clathrin coat assembly protein AP180 (SNAP91).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Clathrin coat assembly protein AP180 (SNAP91).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Clathrin coat assembly protein AP180 (SNAP91).	[32]

References

• [1] A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial of CX-8998, a Selective Modulator of the T-Type Calcium Channel in Inadequately Treated Moderate to Severe Essential Tremor: T-CALM Study Design and Methodology for Efficacy Endpoint and Digital Biomarker Selection.Front Neurol. 2019 Jun 11;10:597. doi: 10.3389/fneur.2019.00597. eCollection 2019.
• [2] The prognosis of CALM-AF10-positive adult T-cell acute lymphoblastic leukemias depends on the stage of maturation arrest.Haematologica. 2013 Nov;98(11):1711-7. doi: 10.3324/haematol.2013.086082. Epub 2013 Jul 5.
• [3] Retroviral insertional mutagenesis identifies Zeb2 activation as a novel leukemogenic collaborating event in CALM-AF10 transgenic mice.Blood. 2010 Feb 11;115(6):1194-203. doi: 10.1182/blood-2009-04-216184. Epub 2009 Dec 9.
• [4] Identification and molecular characterisation of a CALM-AF10 fusion in acute megakaryoblastic leukaemia.Leukemia. 2001 Jun;15(6):910-4. doi: 10.1038/sj.leu.2402140.
• [5] Gene expression profiling and candidate gene resequencing identifies pathways and mutations important for malignant transformation caused by leukemogenic fusion genes.Exp Hematol. 2012 Dec;40(12):1016-27. doi: 10.1016/j.exphem.2012.08.001. Epub 2012 Aug 8.
• [6] A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias.Leukemia. 2015 Feb;29(2):423-32. doi: 10.1038/leu.2014.221. Epub 2014 Jul 16.
• [7] AP180 N-Terminal Homology (ANTH) and Epsin N-Terminal Homology (ENTH) Domains: Physiological Functions and Involvement in Disease.Adv Exp Med Biol. 2019;1111:55-76. doi: 10.1007/5584_2018_218.
• [8] Changed clathrin regulatory proteins in the brains of Alzheimer's disease patients and animal models.J Alzheimers Dis. 2010;22(1):329-42. doi: 10.3233/JAD-2010-100162.
• [9] Who needs more than standard care? Treatment moderators in a randomized clinical trial comparing addiction treatment alone to addiction treatment plus anxiety disorder treatment for comorbid anxiety and substance use disorders.Behav Res Ther. 2018 Aug;107:1-9. doi: 10.1016/j.brat.2018.05.005. Epub 2018 May 17.
• [10] Randomized clinical trial evaluating the preliminary effectiveness of an integrated anxiety disorder treatment in substance use disorder specialty clinics.J Consult Clin Psychol. 2018 Jan;86(1):81-88. doi: 10.1037/ccp0000276.
• [11] Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry. Eur Heart J. 2019 Sep 14;40(35):2964-2975. doi: 10.1093/eurheartj/ehz311.
• [12] Incidence of MLL rearrangement in acute myeloid leukemia, and a CALM-AF10 fusion in M4 type acute myeloblastic leukemia.Leuk Lymphoma. 2002 Jan;43(1):89-95. doi: 10.1080/10428190290000437.
• [13] Novel cleft susceptibility genes in chromosome 6q.J Dent Res. 2010 Sep;89(9):927-32. doi: 10.1177/0022034510370004. Epub 2010 May 28.
• [14] AP180 promotes release site clearance and clathrin-dependent vesicle reformation in mouse cochlear inner hair cells.J Cell Sci. 2020 Jan 22;133(2):jcs236737. doi: 10.1242/jcs.236737.
• [15] COL3A1 and SNAP91: novel glioblastoma markers with diagnostic and prognostic value.Oncotarget. 2016 Oct 25;7(43):70494-70503. doi: 10.18632/oncotarget.12038.
• [16] A CALM-derived nuclear export signal is essential for CALM-AF10-mediated leukemogenesis.Blood. 2013 Jun 6;121(23):4758-68. doi: 10.1182/blood-2012-06-435792. Epub 2013 Mar 13.
• [17] The novel CALM interactor CATS influences the subcellular localization of the leukemogenic fusion protein CALM/AF10.Oncogene. 2006 Jul 6;25(29):4099-109. doi: 10.1038/sj.onc.1209438. Epub 2006 Feb 20.
• [18] Monocytic leukemia with CALM/AF10 rearrangement showing mediastinal emphysema.Am J Hematol. 2003 Feb;72(2):138-42. doi: 10.1002/ajh.10265.
• [19] CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCRgammadelta lineage.Blood. 2003 Aug 1;102(3):1000-6. doi: 10.1182/blood-2002-09-2913. Epub 2003 Apr 3.
• [20] The first Slovak Legius syndrome patient carrying the SPRED1 gene mutation.Gen Physiol Biophys. 2017 Apr;36(2):205-210. doi: 10.4149/gpb_2016032. Epub 2017 Feb 2.
• [21] A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction.Oncogene. 2019 May;38(20):3824-3842. doi: 10.1038/s41388-018-0666-5. Epub 2019 Jan 22.
• [22] Acute myeloid leukemia driven by the CALM-AF10 fusion gene is dependent on BMI1.Exp Hematol. 2019 Jun;74:42-51.e3. doi: 10.1016/j.exphem.2019.04.003. Epub 2019 May 13.
• [23] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [24] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [25] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [26] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [27] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [28] 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.
• [29] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [30] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [31] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [32] 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.