Details of Drug Off-Target (DOT)

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

• DOT Name: EF-hand calcium-binding domain-containing protein 4B (CRACR2A)
• Synonyms: Calcium release-activated calcium channel regulator 2A; CRAC channel regulator 2A; Calcium release-activated channel regulator 2A; Ras-related protein Rab-46
• Gene Name: CRACR2A
• Related Disease:
  Liver cirrhosis
  Non-alcoholic fatty liver disease
  Periodontitis
  Acute myelogenous leukaemia
  Nervous system inflammation
  Periodontal disease
• UniProt ID: EFC4B_HUMAN
• PDB ID: 6PSD
• Pfam ID: PF13499 ; PF00071
• Sequence:
  MAAPDGRVVSRPQRLGQGSGQGPKGSGACLHPLDSLEQKETQEQTSGQLVMLRKAQEFFQ
  TCDAEGKGFIARKDMQRLHKELPLSLEELEDVFDALDADGNGYLTPQEFTTGFSHFFFSQ
  NNPSQEDAGEQVAQRHEEKVYLSRGDEDLGDMGEDEEAQFRMLMDRLGAQKVLEDESDVK
  QLWLQLKKEEPHLLSNFEDFLTRIISQLQEAHEEKNELECALKRKIAAYDEEIQHLYEEM
  EQQIKSEKEQFLLKDTERFQARSQELEQKLLCKEQELEQLTQKQKRLEGQCTALHHDKHE
  TKAENTKLKLTNQELARELERTSWELQDAQQQLESLQQEACKLHQEKEMEVYRVTESLQR
  EKAGLLKQLDFLRERNKHLRDERDICFQKNKAAKANTAASRASWKKRSGSVIGKYVDSRG
  ILRSQSEEEEEVFGIPRRSSLGLSGYPLTEEEPGTGEPGPGGPYPRPLRRIISVEEDPLP
  QLLDGGFEQPLSKCSEEEEVSDQGVQGQIPEAPPLKLTPTSPRGQPVGKEALCKEESSPS
  APDRLFKIVFVGNSAVGKTSFLRRFCEDRFSPGMAATVGIDYRVKTLNVDNSQVALQLWD
  TAGQERYRCITQQFFRKADGVIVMYDLTDKQSFLSVRRWLSSVEEAVGDRVPVLLLGNKL
  DNEKEREVPRGLGEQLATENNLIFYECSAYSGHNTKESLLHLARFLKEQEDTVREDTIQV
  GHPAKKKSCCG
• Function: [Isoform 1]: Ca(2+)-binding protein that plays a key role in store-operated Ca(2+) entry (SOCE) in T-cells by regulating CRAC channel activation. Acts as a cytoplasmic calcium-sensor that facilitates the clustering of ORAI1 and STIM1 at the junctional regions between the plasma membrane and the endoplasmic reticulum upon low Ca(2+) concentration. It thereby regulates CRAC channel activation, including translocation and clustering of ORAI1 and STIM1. Upon increase of cytoplasmic Ca(2+) resulting from opening of CRAC channels, dissociates from ORAI1 and STIM1, thereby destabilizing the ORAI1-STIM1 complex; [Isoform 2]: Rab GTPase that mediates the trafficking of Weibel-Palade bodies (WPBs) to microtubule organizing center (MTOC) in endothelial cells in response to acute inflammatory stimuli. During histamine (but not thrombin) stimulation of endothelial cells, the dynein-bound form induces retrograde transport of a subset of WPBs along microtubules to the MTOC in a Ca(2+)-independent manner and its GTPase activity is essential for this function. Ca(2+)-regulated dynein adapter protein that activates dynein-mediated transport and dynein-dynactin motility on microtubules and regulates endosomal trafficking of CD47. Acts as an intracellular signaling module bridging two important T-cell receptor (TCR) signaling pathways, Ca(2+)-NFAT and JNK, to affect T-cell activation. In resting T-cells, is predominantly localized near TGN network in a GTP-bound form, upon TCR stimulation, localizes at the immunological synapse via interaction with VAV1 to activate downstream Ca(2+)-NFAT and JNK signaling pathways. Plays a role in T-helper 1 (Th1) cell differentiation and T-helper 17 (Th17) cell effector function. Plays a role in store-operated Ca(2+) entry (SOCE) in T-cells by regulating CRAC channel activation.
• Tissue Specificity: .Expressed in the Jurkat T-cell line.; [Isoform 2]: Expressed in endothelial cells . Expressed in Weibel-Palade bodies (which are P-selectin/SELP negative) in endothelial cells . Expressed in the Jurkat T-cell line .
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[1]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[1]
Periodontitis	DISI9JOI	moderate	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[3]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[4]
Periodontal disease	DISJQHVN	Limited	Genetic Variation	[2]

1 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 EF-hand calcium-binding domain-containing protein 4B (CRACR2A).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of EF-hand calcium-binding domain-containing protein 4B (CRACR2A).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of EF-hand calcium-binding domain-containing protein 4B (CRACR2A).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of EF-hand calcium-binding domain-containing protein 4B (CRACR2A).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of EF-hand calcium-binding domain-containing protein 4B (CRACR2A).	[9]

References

• [1] Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease.Gastroenterology. 2010 Nov;139(5):1567-76, 1576.e1-6. doi: 10.1053/j.gastro.2010.07.057. Epub 2010 Aug 11.
• [2] A genome-wide association study identifies an association between variants in EFCAB4B gene and periodontal disease in an Italian isolated population.J Periodontal Res. 2018 Dec;53(6):992-998. doi: 10.1111/jre.12598. Epub 2018 Oct 4.
• [3] 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.
• [4] CRACR2A-Mediated TCR Signaling Promotes Local Effector Th1 and Th17 Responses.J Immunol. 2018 Aug 15;201(4):1174-1185. doi: 10.4049/jimmunol.1800659. Epub 2018 Jul 9.
• [5] 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.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.