Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUTY2ED)

• DOT Name: Signal peptide peptidase-like 2C (SPPL2C)
• Synonyms: SPP-like 2C; SPPL2c; EC 3.4.23.-; Intramembrane protease 5; IMP-5
• Gene Name: SPPL2C
• Related Disease:
  Chronic obstructive pulmonary disease
  Corticobasal degeneration
  Parkinson disease
  Primary biliary cholangitis
  Alopecia
  Androgenetic alopecia
  Baldness, male pattern
• UniProt ID: SPP2C_HUMAN
• EC Number: 3.4.23.-
• Pfam ID: PF02225 ; PF04258
• Sequence:
  MACLGFLLPVGFLLLISTVAGGKYGVAHVVSENWSKDYCILFSSDYITLPRDLHHAPLLP
  LYDGTKAPWCPGEDSPHQAQLRSPSQRPLRQTTAMVMRGNCSFHTKGWLAQGQGAHGLLI
  VSRVSDQQCSDTTLAPQDPRQPLADLTIPVAMLHYADMLDILSHTRGEAVVRVAMYAPPE
  PIIDYNMLVIFILAVGTVAAGGYWAGLTEANRLQRRRARRGGGSGGHHQLQEAAAAEGAQ
  KEDNEDIPVDFTPAMTGVVVTLSCSLMLLLYFFYDHFVYVTIGIFGLGAGIGLYSCLSPL
  VCRLSLRQYQRPPHSLWASLPLPLLLLASLCATVIIFWVAYRNEDRWAWLLQDTLGISYC
  LFVLHRVRLPTLKNCSSFLLALLAFDVFFVFVTPFFTKTGESIMAQVALGPAESSSHERL
  PMVLKVPRLRVSALTLCSQPFSILGFGDIVVPGFLVAYCCRFDVQVCSRQIYFVACTVAY
  AVGLLVTFMAMVLMQMGQPALLYLVSSTLLTSLAVAACRQELSLFWTGQGRAKMCGLGCA
  PSAGSRQKQEGAADAHTASTLERGTSRGAGDLDSNPGEDTTEIVTISENEATNPEDRSDS
  SEGWSDAHLDPNELPFIPPGASEELMPLMPMAMLIPLMPLMPPPSELGHVHAQAQAHETG
  LPWAGLHKRKGLKVRKSMSTQAPL
• Function: Sperm-specific intramembrane-cleaving aspartic protease (I-CLiP) that cleaves distinct tail-anchored proteins and SNARE proteins. In elongated spermatids, modulates intracellular Ca(2+) homeostasis by controlling PLN abundance through proteolytic cleavage. During spermatogenesis, processes SNARE proteins and impacts vesicular trafficking which supports compartmental reorganization in maturating spermatids and may play a role in formation of the acrosome ; In round spermatids, acts as a scaffold protein supporting FREY1 in IZUMO1 recruitment at the endoplasmic reticulum membrane and coordination of IZUMO1 complex assembly. Stabilizes FREY1 at the endoplasmic reticulum membrane through interaction. May recruit IZUMO1 interaction partners.
• Tissue Specificity: Highly expressed in testis where it is primarily localised in spermatids (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[1]
Corticobasal degeneration	DISSMOTT	Strong	Genetic Variation	[2]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[3]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[4]
Alopecia	DIS37HU4	Limited	Genetic Variation	[5]
Androgenetic alopecia	DISSJR1P	Limited	Genetic Variation	[6]
Baldness, male pattern	DIS9C9RO	Limited	Genetic Variation	[6]

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 Signal peptide peptidase-like 2C (SPPL2C).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Signal peptide peptidase-like 2C (SPPL2C).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Signal peptide peptidase-like 2C (SPPL2C).	[9]

References

• [1] Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
• [2] Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy.Nat Commun. 2015 Jun 16;6:7247. doi: 10.1038/ncomms8247.
• [3] Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes.Hum Mol Genet. 2014 Sep 1;23(17):4693-702. doi: 10.1093/hmg/ddu158. Epub 2014 May 19.
• [4] Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis.Nat Genet. 2012 Oct;44(10):1137-41. doi: 10.1038/ng.2395. Epub 2012 Sep 9.
• [5] Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
• [6] Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.PLoS Genet. 2012 May;8(5):e1002746. doi: 10.1371/journal.pgen.1002746. Epub 2012 May 31.
• [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] Aberrantly expressed genes in HaCaT keratinocytes chronically exposed to arsenic trioxide. Biomark Insights. 2011 Feb 8;6:7-16.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.