Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9SGF3X)

• DOT Name: Signal recognition particle subunit SRP54 (SRP54)
• Synonyms: EC 3.6.5.4; Signal recognition particle 54 kDa protein
• Gene Name: SRP54
• Related Disease:
  Leukopenia
  Neutropenia, severe congenital, 8, autosomal dominant
  Rheumatoid arthritis
  Shwachman-Diamond syndrome 1
  Systemic lupus erythematosus
  Autosomal dominant severe congenital neutropenia
  Shwachman-Diamond syndrome
• UniProt ID: SRP54_HUMAN
• PDB ID: 1MFQ; 1QB2; 5L3Q; 6Y2Z; 6Y30; 6Y31; 6Y32; 7NFX; 7QWQ
• EC Number: 3.6.5.4
• Pfam ID: PF00448 ; PF02881 ; PF02978
• Sequence:
  MVLADLGRKITSALRSLSNATIINEEVLNAMLKEVCTALLEADVNIKLVKQLRENVKSAI
  DLEEMASGLNKRKMIQHAVFKELVKLVDPGVKAWTPTKGKQNVIMFVGLQGSGKTTTCSK
  LAYYYQRKGWKTCLICADTFRAGAFDQLKQNATKARIPFYGSYTEMDPVIIASEGVEKFK
  NENFEIIIVDTSGRHKQEDSLFEEMLQVANAIQPDNIVYVMDASIGQACEAQAKAFKDKV
  DVASVIVTKLDGHAKGGGALSAVAATKSPIIFIGTGEHIDDFEPFKTQPFISKLLGMGDI
  EGLIDKVNELKLDDNEALIEKLKHGQFTLRDMYEQFQNIMKMGPFSQILGMIPGFGTDFM
  SKGNEQESMARLKKLMTIMDSMNDQELDSTDGAKVFSKQPGRIQRVARGSGVSTRDVQEL
  LTQYTKFAQMVKKMGGIKGLFKGGDMSKNVSQSQMAKLNQQMAKMMDPRVLHHMGGMAGL
  QSMMRQFQQGAAGNMKGMMGFNNM
• Function: Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). As part of the SRP complex, associates with the SRP receptor (SR) component SRPRA to target secretory proteins to the endoplasmic reticulum membrane. Binds to the signal sequence of presecretory proteins when they emerge from the ribosomes. Displays basal GTPase activity, and stimulates reciprocal GTPase activation of the SR subunit SRPRA. Forms a guanosine 5'-triphosphate (GTP)-dependent complex with the SR subunit SRPRA. SR compaction and GTPase mediated rearrangement of SR drive SRP-mediated cotranslational protein translocation into the ER. Requires the presence of SRP9/SRP14 and/or SRP19 to stably interact with RNA. Plays a role in proliferation and differentiation of granulocytic cells, neutrophils migration capacity and exocrine pancreas development.
• KEGG Pathway: Protein export (hsa03060)
• Reactome Pathway: SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukopenia	DISJMBMM	Strong	Genetic Variation	[1]
Neutropenia, severe congenital, 8, autosomal dominant	DISDESQ0	Strong	Autosomal dominant	[1]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[2]
Shwachman-Diamond syndrome 1	DISRH3TQ	Strong	CausalMutation	[1]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[2]
Autosomal dominant severe congenital neutropenia	DISZC7BV	Supportive	Autosomal dominant	[3]
Shwachman-Diamond syndrome	DISW57NW	Supportive	Autosomal recessive	[1]

8 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 Signal recognition particle subunit SRP54 (SRP54).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Signal recognition particle subunit SRP54 (SRP54).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Signal recognition particle subunit SRP54 (SRP54).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Signal recognition particle subunit SRP54 (SRP54).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Signal recognition particle subunit SRP54 (SRP54).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Signal recognition particle subunit SRP54 (SRP54).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Signal recognition particle subunit SRP54 (SRP54).	[10]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of Signal recognition particle subunit SRP54 (SRP54).	[11]

References

• [1] Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features. J Clin Invest. 2017 Nov 1;127(11):4090-4103. doi: 10.1172/JCI92876. Epub 2017 Oct 3.
• [2] Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis.Ann Rheum Dis. 2018 Jul;77(7):1063-1069. doi: 10.1136/annrheumdis-2017-212614. Epub 2018 Mar 7.
• [3] Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome. Blood. 2018 Sep 20;132(12):1318-1331. doi: 10.1182/blood-2017-12-820308. Epub 2018 Jun 18.
• [4] 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.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] 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.
• [8] 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.
• [9] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [10] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [11] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.