EVI5L

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Wikidata
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EVI5L (Ecotropic Viral Integration Site 5-Like) is a protein that in humans is encoded by the EVI5L gene.[1] EVI5L is a member of the Ras superfamily of monomeric guanine nucleotide-binding (G) proteins, and functions as a GTPase-activating protein (GAP) with a broad specificity.[2][3] Measurement of in vitro Rab-GAP activity has shown that EVI5L has significant Rab2A- and Rab10-GAP activity.[4]

Gene

The EVI5L gene is 34,701 base pairs long and has an unprocessed mRNA that is 3,756 nucleotides in length. It consists of 19 exons that encode for an 805 amino acid protein.[5]

File:Location of EVI5L on Chromosome 19.png
Relative location of EVI5L on the short arm of Chromosome 19

Locus

EVI5L is located on the short arm (p) of chromosome 19 in region 1, band 3, and sub-band 2 (19p13.2) starting at 7,830,275 base pairs and ending at 7,864,976 base pairs. It is encoded for on the plus strand. It is located near the CLEC4M (C-type lectin domain family 4, member M) gene, which is involved in peptide antigen transport.[6]

Homology and Evolution

Homologous domains

EVI5L contains a RAB-GAP TBC domain, which is involved with regulating membrane trafficking by cycling between inactive (GDP-bound) and active (GTP-bound) conformations.[7] It also has the apolipophorin-III and tetratricopeptide repeat (TPR) domains. Apolipophorin-III play vital roles in the transport of lipids and lipoprotein metabolism,[8] while TPR mediates protein-protein interactions and the assembly of multi protein complexes.[9] These three domains are highly conserved in EVI5L orthologs.

Paralogs

There are 7 moderately related proteins in humans that are paralogous to the RAB-GAP TBC domain of EVI5L. All of these proteins are in the guanosine nucleotide-binding protein family[10]

Paralogs of EVI5L
Paralogous Protein Protein Name Sequence Length (amino acids) Amino Acid Identity
EVI5 Ecotropic viral integration site 5 810 aa 51%
TBC1D14 TBC1 domain family, member 14 693 aa 19%
RABGAP1 RAB GTPase activating protein 1 1069 aa 18%
RABGAP1L RAB GTPase activating protein 1-like 815 aa 18%
TBC1D12 TBC1 Domain Family Member 12 775 aa 17%
TBC1 (Tre-2/USP6, BUB2, Cdc16) Domain Family, Member 1 1168 aa 15%
TBC1D4 TBC1 domain family, member 4 1298 aa 13%

Orthologs

There are 63[11] orthologs of EVI5L that have been identified including mammals, birds, reptiles, and fish.[12] EVI5L is highly conserved among its orthologs but is not present in insects, plants, bacteria, archea or protists.

Homologs

File:Amino acid sequence identity vs time since species divergence for orthologs of EVI5L.png
Amino acid sequence identity vs. time since species divergence for orthologs of EVI5L. It is seen that EVI5L has moderate/fast evolution rate when compared to Cytochrome C and H3 histone.

The following table lists the homologs of EVI5L:

Genus and Species Common Name Accession Number Seq.
Length		 Seq.
Identity		 Seq.
Similarity		 Time of Divergence
Homo sapiens Humans NM_001159944.2 3756 bp - - -
Pan troglodytes Common Chimpanzee XM_003316056.2 3874 bp 99% 99% 6.3 mya
Canis familiaris Dog XM_003432793.1 2430 bp 98% 99% 94.2 mya
Sus scrofa Wild Boar XM_003123194 3673 bp 95% 99% 94.2 mya
Chelonia mydas Sea Turtle EMP36617 3436 bp 94% 99% 294.5 mya
Alligator sinensis Chinese Alligator XM_006036467.1 6780 bp 82% 91% 296.4 mya
Ficedula albicollis Collared Flycatcher XM_005062373.1 2090 bp 79% 88% 324.2 mya
Haplochromis burtoni Cichlid XM_005934450.1 6638 bp 70% 84% 400.1 mya
Danio rerio Zebrafish XM_689590 2856 bp 69% 82% 400.1 mya
Oreochromis niloticus Nile Tilapia XM_003447957 6757 bp 68% 84% 400.1 mya

Protein

The protein of EVI5L consists of 805[13] amino acid residues. The molecular weight of the mature protein is 92.5 kdal with an isoelectric point of 5.05. EVI5L has an unusually large amount of glutamic acid residues, compared to similar proteins. Most of the protein is neutral, with no positive charge, negative charge, or mixed charge clusters.[14] It has a very small negative hydrophobicity (-0.597019). EVI5L is a soluble protein[15] that localizes in the nucleus.[16] It contains no signal peptide, no mitochondrial targeting motifs and no peroxisomal targeting signal in the C-terminus. There is no transmembrane domain in EVI5L.[17]

Isoforms

EVI5L has two isoforms produced by alternative splicing. Isoform 2 is missing in-frame exon 11, making it shorter (794 amino acids).[18]

File:Domains and post-translational modifications of EVI5L.png
Important domains and post-translational modifications of EVI5L

Post-Translational Modifications

Post translational modifications of EVI5L that are evolutionarily conserved in majority of the orthologs include glycosylation (C-mannosylation),[19] glycation,[20] phosphorylation (non-kinase and kinase specific),[21][22] and sumoylation.[23] There is also one leucine-rich nuclear export signal.[24]

File:Predicted Secondary Structure of EVI5L.png
Highly conserved regions of RAB-GAP1L correspond to the RAB-GAP TBC domain in EVI5L. The conserved regions are next to each other, and form a pocket for possible interactions with RAB2A and RAB10. There are no beta-sheets present, just alpha helices.

Secondary Structure

The entire secondary structure of EVI5L is made up of alpha helices, with no beta sheets present.[25][26] This is also true for EVI5Ls closest structural paralog, RABGAP1L.[27]

Expression

Promoter

The predicted promoter for the EVI5L gene spans 664 base pairs from 7,910,867 to 7,911,530 with a predicted transcriptional start site that is 114 base pairs and spans from 7,911,346 to 7,911,460.[28] The promoter region and beginning of the EVI5L gene (7,910,997 to 7,911,843) is not conserved past primates. This region was used to determine transcription factor interactions.

Some of the main transcription factors predicted to bind to the promoter includes: activator-, mediator- and TBP-dependent core promoter element for RNA polymerase II transcription from TATA-less promoters, p53 tumor suppressor, brachyury gene, mesoderm developmental factor, EGR/nerve growth factor induced protein C & related factors, and GLI zinc finger family.[29]

File:Expression in EVI5L.png
EVI5L has ubiquitously low expression, with slightly higher expression in the testis and fetal brain.

Expression

Expression data from expressed sequence tag mapping, microarray and in situ hybridization shows EVI5L has ubiquitously low expression.[30][31][32] However, it has slightly higher expression in the testis and fetal brain.

Function and Biochemistry

The exact function of EVI5L is unknown. Given this, the paralogs of the gene are associated with starvation-induced autophagosome formation and trafficking and translocation of GLUT4-containing vesicles.[33][34] Therefore, EVI5L is predicted to target endocytic vesicles.

Interacting Proteins

File:EVI5L phosphorylation sites.png
SRPK2 phosphorylates the serine residues of EVI5L

EVI5L has been shown to interact with NUDT18 (nucleoside diphosphate linked moiety X)-type motif 18[35] and SRPK2 (serine/threonine-protein kinase 2).[36] NUDT18 is a member of the Nudix hydrolase family. Nudix hydrolases eliminate potentially toxic nucleotide metabolites from the cell and regulate the concentrations and availability of many different nucleotide substrates, cofactors, and signaling molecules.[37] SRPK2 is a Serine/arginine rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing.[38]

Clinical significance

Zebrafish deficient for Rab23 or its GTPase-activating protein, EVI5L, exhibit abnormal heart formation. This is attributed to the requirement of RAB23 in the differentiation of cardiac progenitor cells. RAB23 is required for normal development of the brain, spinal cord and heart, and without EVI5L to activate RAB23, abnormal formation of these organs ensues.[39]

References

  1. ↑ "Entrez Gene, EVI5L". NCBI. Retrieved 2014-04-22.
  2. ↑ "Uniprot: EVI5L".
  3. ↑ Faitar SL, Kilijanski JJ, Heassler KW, Davie JJ (April 2013). "The identification, characterization, and subcellular localization of a novel potential GTPase activating protein involved in cytokinesis". Federation of American Societies for Experimental Biology. 27 (1046): 2. doi:10.1096/fj.1530-6860.
  4. ↑ Itoh T, Satoh M, Kanno E, Fukuda M (September 2006). "Screening for target Rabs of TBC (Tre-2/Bub2/Cdc16) domain-containing proteins based on their Rab-binding activity". Genes to Cells. 11 (9): 1023–37. doi:10.1111/j.1365-2443.2006.00997.x. PMID 16923123.
  5. ↑ National Center for Biotechnology Information EntrezGene reference information for EVI5L ecotropic viral integration site 5-like (Homo sapiens)
  6. ↑ Chromosome-centric Human Proteome Project Chromosome-centric Human Proteome Project, EVI5L (Homo sapiens)
  7. ↑ Pan X, Eathiraj S, Munson M, Lambright DG (July 2006). "TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism". Nature. 442 (7100): 303–6. doi:10.1038/nature04847. PMID 16855591.
  8. ↑ National Center for Biotechnology Information: Conserved Domains Database (CDD) and Resource Group Conserved domains for EVI5L ecotropic viral integration site 5-like (Homo sapiens)
  9. ↑ D'Andrea LD, Regan L (December 2003). "TPR proteins: the versatile helix". Trends in Biochemical Sciences. 28 (12): 655–62. doi:10.1016/j.tibs.2003.10.007. PMID 14659697.
  10. ↑ Ensembl Paralogs, EVI5L (Homo sapiens)
  11. ↑ European Bioinformatics Institute Orthologs, EVI5L (Homo sapiens)
  12. ↑ Ensembl Orthologs, EVI5L (Homo sapiens)
  13. ↑ National Center for Biotechnology Information: Protein EVI5-like protein isoform 1
  14. ↑ SDSC Biology Workbench: SAPS [workbench.sdsc.edu EVI5L Statistical Analysis of Protein Sequences]
  15. ↑ SOSUI: classification and secondary structure prediction
  16. ↑ PSORTII: Localization of proteins in yeast and animal cells Localization of proteins in yeast and animal cells: EVI5L
  17. ↑ TMHMM:Prediction of transmembrane helices in proteins EVI5L Transmembrane Domain
  18. ↑ Origene Isoforms, EVI5L (Homo sapiens)
  19. ↑ NetCGlyc 1.0: Prediction of mammalian C-mannosylation sites.C-mannosylation in EVI5L
  20. ↑ NetGlycate: Predicts glycation of ε amino groups of lysines in mammalian proteins NetGlycate: Predicts glycation in EVI5L
  21. ↑ NetPhos: Produces neural network predictions for serine, threonine and tyrosine phosphorylation sites in eukaryotic proteins. Phosphorylation sites in EVI5L
  22. ↑ NetPhosK: Preduces neural network predictions of kinase specific eukaryotic protein phosphoylation sites Kinase-specific Phosphorylation sites in EVI5L
  23. ↑ SUMOplot™ Analysis Program: Predicts and scores sumoylation sites Sumoylation sites in EVI5L
  24. ↑ NetNES: Predicts leucine-rich nuclear export signals (NES) in eukaryotic proteins Leucine-rich nuclear export signals (NES) in EVI5L
  25. ↑ CHOFAS: Secondary structure prediction program CHOFAS: secondary structure in EVI5L
  26. ↑ PELE: Secondary structure prediction program PELE: secondary structure in EVI5L
  27. ↑ National Center for Biotechnology Information: Structure Structure of RabGap1L
  28. ↑ "El Durado (Genomatix)".
  29. ↑ "El Durado-Genomatix".
  30. ↑ "Unigene NCBI".
  31. ↑ "GEO Profiles NCBI".
  32. ↑ "Bio GPS".
  33. ↑ GeneCards: TBC1 Domain Family, Member 14 TBC1 Domain Family, Member 14 Function
  34. ↑ GeneCards: TBC1 (Tre-2/USP6, BUB2, Cdc16) Domain Family, Member 1 BC1 (Tre-2/USP6, BUB2, Cdc16) Domain Family, Member 1 Function
  35. ↑ STRING - Known and Predicted Protein-Protein Interactions NUDT18 and EVI5L interaction
  36. ↑ IntAct: molecular interaction data SRPK2 and EVI5L interaction
  37. ↑ GeneCards: NUDT18 (nucleoside diphosphate linked moiety X)-type motif 18 NUDT18 (nucleoside diphosphate linked moiety X)-type motif 18 Function
  38. ↑ SRPK2 (serine/threonine-protein kinase 2) SRPK2 (serine/threonine-protein kinase 2) Function
  39. ↑ Jenkins D, Beales PL, Wilkie AO (May 2012). "Rab23 is required for cardiac progenitor cell differentiation and positively-regulates Wnt11/AP-1 signalling in zebrafish". International Cilia in Development and Disease Scientific Conference.

Further reading

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