EVI5L (Ecotropic Viral Integration Site 5-Like) is a protein that in humans is encoded by the EVI5L gene. 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. Measurement of in vitro Rab-GAP activity has shown that EVI5L has significant Rab2A- and Rab10-GAP activity.
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.National Center for Biotechnology Information EntrezGene reference information for EVI5L ecotropic viral integration site 5-like (Homo sapiens)
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.Chromosome-centric Human Proteome Project Chromosome-centric Human Proteome Project, EVI5L (Homo sapiens)
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. It also has the apolipophorin-III and tetratricopeptide repeat (TPR) domains. Apolipophorin-III play vital roles in the transport of lipids and lipoprotein metabolism,National Center for Biotechnology Information: Conserved Domains Database (CDD) and Resource Group Conserved domains for EVI5L ecotropic viral integration site 5-like (Homo sapiens) while TPR mediates protein-protein interactions and the assembly of multi protein complexes. 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 familyEnsembl Paralogs, EVI5L (Homo sapiens) +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 63European Bioinformatics Institute Orthologs, EVI5L (Homo sapiens) orthologs of EVI5L that have been identified including mammals, birds, reptiles, and fish.Ensembl Orthologs, EVI5L (Homo sapiens) EVI5L is highly conserved among its orthologs but is not present in insects, plants, bacteria, archea or protists.
Homologs
The following table lists the homologs of EVI5L:
Genus and Species Common name Accession number Seq.Length Seq.Identity Seq.Similarity Time of DivergenceHomo sapiensHumansNM_001159944.23756 bp---Pan troglodytesCommon ChimpanzeeXM_003316056.23874 bp99%99%6.3 myaCanis familiarisDogXM_003432793.12430 bp98%99%94.2 myaSus scrofaWild BoarXM_0031231943673 bp95%99%94.2 myaChelonia mydasSea TurtleEMP366173436 bp94%99%294.5 myaAlligator sinensisChinese AlligatorXM_006036467.16780 bp82%91%296.4 myaFicedula albicollisCollared FlycatcherXM_005062373.12090 bp79%88%324.2 myaHaplochromis burtoniCichlidXM_005934450.16638 bp70%84%400.1 myaDanio rerioZebrafishXM_6895902856 bp69%82%400.1 myaOreochromis niloticusNile TilapiaXM_0034479576757 bp68%84%400.1 mya
Protein
The protein of EVI5L consists of 805National Center for Biotechnology Information: Protein EVI5-like protein isoform 1 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.SDSC Biology Workbench: SAPS [workbench.sdsc.edu EVI5L Statistical Analysis of Protein Sequences] It has a very small negative hydrophobicity (-0.597019). EVI5L is a soluble protein that localizes in the nucleus.PSORTII: Localization of proteins in yeast and animal cells Localization of proteins in yeast and animal cells: EVI5L 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.TMHMM:Prediction of transmembrane helices in proteins EVI5L Transmembrane Domain
Isoforms
EVI5L has two isoforms produced by alternative splicing. Isoform 2 is missing in-frame exon 11, making it shorter (794 amino acids).Origene Isoforms, EVI5L (Homo sapiens)
Post-translational modifications
Post translational modifications of EVI5L that are evolutionarily conserved in majority of the orthologs include glycosylation (C-mannosylation),NetCGlyc 1.0: Prediction of mammalian C-mannosylation sites. C-mannosylation in EVI5L glycation,NetGlycate: Predicts glycation of ε amino groups of lysines in mammalian proteins NetGlycate: Predicts glycation in EVI5L phosphorylation (non-kinase and kinase specific),NetPhos: Produces neural network predictions for serine, threonine and tyrosine phosphorylation sites in eukaryotic proteins. Phosphorylation sites in EVI5LNetPhosK: Produces neural network predictions of kinase specific eukaryotic protein phosphorylation sites Kinase-specific Phosphorylation sites in EVI5L and sumoylation.SUMOplot™ Analysis Program: Predicts and scores sumoylation sites Sumoylation sites in EVI5L There is also one leucine-rich nuclear export signal.NetNES: Predicts leucine-rich nuclear export signals (NES) in eukaryotic proteins Leucine-rich nuclear export signals (NES) in EVI5L
Secondary structure
The entire secondary structure of EVI5L is made up of alpha helices, with no beta sheets present.CHOFAS: Secondary structure prediction program CHOFAS: secondary structure in EVI5LPELE: Secondary structure prediction program PELE: secondary structure in EVI5L This is also true for EVI5Ls closest structural paralog, RABGAP1L.National Center for Biotechnology Information: Structure Structure of RabGap1L
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. 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.
Expression
Expression data from expressed sequence tag mapping, microarray and in situ hybridization shows EVI5L has ubiquitously low expression. 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.GeneCards: TBC1 Domain Family, Member 14 TBC1 Domain Family, Member 14 FunctionGeneCards: TBC1 (Tre-2/USP6, BUB2, Cdc16) Domain Family, Member 1 BC1 (Tre-2/USP6, BUB2, Cdc16) Domain Family, Member 1 Function Therefore, EVI5L is predicted to target endocytic vesicles.
Interacting proteins
EVI5L has been shown to interact with NUDT18 (nucleoside diphosphate linked moiety X)-type motif 18STRING - Known and Predicted Protein-Protein Interactions NUDT18 and EVI5L interaction and SRPK2 (serine/threonine-protein kinase 2).IntAct: molecular interaction data SRPK2 and EVI5L interaction 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.GeneCards: NUDT18 (nucleoside diphosphate linked moiety X)-type motif 18 NUDT18 (nucleoside diphosphate linked moiety X)-type motif 18 Function 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.SRPK2 (serine/threonine-protein kinase 2) SRPK2 (serine/threonine-protein kinase 2) Function
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.
References
Further reading