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An Error has occurred retrieving Wikidata item for infobox 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
[edit]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 a 805 amino acid protein.[5]
![](http://upload.wikimedia.org/wikipedia/commons/5/5f/Location_of_EVI5L_on_Chromosome_19.png)
Locus
[edit]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
[edit]Homologous domains
[edit]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
[edit]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]
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
[edit]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
[edit]![](http://upload.wikimedia.org/wikipedia/commons/thumb/4/4b/Amino_Acid_Sequence_Identity_vs._Time_since_species_Divergence.png/220px-Amino_Acid_Sequence_Identity_vs._Time_since_species_Divergence.png)
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
[edit]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
[edit]EVI5L has two isoforms produced by alternative splicing. Isoform 2 is missing in-frame exon 11, making it shorter (794 amino acids).[18]
![](http://upload.wikimedia.org/wikipedia/commons/thumb/9/9d/Domains_and_post-translational_modifications_of_EVI5L.png/220px-Domains_and_post-translational_modifications_of_EVI5L.png)
Post-Translational Modifications
[edit]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]
![](http://upload.wikimedia.org/wikipedia/commons/b/b8/Predicted_Secondary_Structure_of_EVI5L.png)
Secondary Structure
[edit]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
[edit]Promoter
[edit]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]
![](http://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/Expression_in_EVI5L.png/220px-Expression_in_EVI5L.png)
Expression
[edit]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
[edit]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
[edit]![](http://upload.wikimedia.org/wikipedia/commons/thumb/6/65/EVI5L_phosphorylation_sites.png/220px-EVI5L_phosphorylation_sites.png)
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
[edit]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
[edit]- ^ "Entrez Gene, EVI5L". NCBI. Retrieved 2014-04-22.
- ^ "Uniprot: EVI5L".
- ^ Silviu Leonard Faitar, Jordan J Kilijanski, Kyle W Heassler and Jeremiah J Davie (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.
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: CS1 maint: multiple names: authors list (link) - ^ Takashi Itoh, Megumi Satoh, Eiko Kanno and Mitsunori Fukuda (July 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): 1023–1037. doi:10.1111/j.1365-2443.2006.00997.x. PMID 16923123.
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: CS1 maint: multiple names: authors list (link) - ^ National Center for Biotechnology Information EntrezGene reference information for EVI5L ecotropic viral integration site 5-like (Homo sapiens)
- ^ Chromosome-centric Human Proteome Project Chromosome-centric Human Proteome Project, EVI5L (Homo sapiens)
- ^ Xiaojing Pan, Sudharshan Eathiraj, Mary Munson and David G. Lambright (July 2006). "TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism". Nature. 442: 303–306. doi:10.1038/nature04847.
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: CS1 maint: multiple names: authors list (link) - ^ National Center for Biotechnology Information: Conserved Domains Database (CDD) and Resource Group Conserved domains for EVI5L ecotropic viral integration site 5-like (Homo sapiens)
- ^ Luca D. D'Andrea, Lynne Regan (December 2003). "TPR proteins: the versatile helix". Trends in Biochemical Sciences. 28 (12): 655–662. doi:http://dx.doi.org/10.1016/j.tibs.2003.10.007.
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- ^ Ensembl Paralogs, EVI5L (Homo sapiens)
- ^ European Bioinformatics Institute Orthologs, EVI5L (Homo sapiens)
- ^ Ensembl Orthologs, EVI5L (Homo sapiens)
- ^ National Center for Biotechnology Information: Protein EVI5-like protein isoform 1
- ^ SDSC Biology Workbench: SAPS [workbench.sdsc.edu EVI5L Statistical Analysis of Protein Sequences]
- ^ SOSUI: classification and secondary structure prediction [1]
- ^ PSORTII: Localization of proteins in yeast and animal cells [http://psort.hgc.jp/form2.html Localization of proteins in yeast and animal cells: EVI5L]
- ^ TMHMM:Prediction of transmembrane helices in proteins EVI5L Transmembrane Domain
- ^ Origene Isoforms, EVI5L (Homo sapiens)
- ^ NetCGlyc 1.0: Prediction of mammalian C-mannosylation sites.C-mannosylation in EVI5L
- ^ NetGlycate: Predicts glycation of ε amino groups of lysines in mammalian proteins NetGlycate: Predicts glycation in EVI5L
- ^ NetPhos: Produces neural network predictions for serine, threonine and tyrosine phosphorylation sites in eukaryotic proteins. Phosphorylation sites in EVI5L
- ^ NetPhosK: Preduces neural network predictions of kinase specific eukaryotic protein phosphoylation sites Kinase-specific Phosphorylation sites in EVI5L
- ^ SUMOplot™ Analysis Program: Predicts and scores sumoylation sites Sumoylation sites in EVI5L
- ^ NetNES: Predicts leucine-rich nuclear export signals (NES) in eukaryotic proteins Leucine-rich nuclear export signals (NES) in EVI5L
- ^ CHOFAS: Secondary structure prediction program CHOFAS: secondary structure in EVI5L
- ^ PELE: Secondary structure prediction program PELE: secondary structure in EVI5L
- ^ National Center for Biotechnology Information: Structure Structure of RabGap1L
- ^ "El Durado (Genomatix)".
- ^ "El Durado-Genomatix".
- ^ "Unigene NCBI".
- ^ "GEO Profiles NCBI".
- ^ "Bio GPS".
- ^ GeneCards: TBC1 Domain Family, Member 14 TBC1 Domain Family, Member 14 Funtion
- ^ GeneCards: TBC1 (Tre-2/USP6, BUB2, Cdc16) Domain Family, Member 1 BC1 (Tre-2/USP6, BUB2, Cdc16) Domain Family, Member 1 Function
- ^ STRING - Known and Predicted Protein-Protein Interactions NUDT18 and EVI5L interaction
- ^ IntAct: molecular interaction data SRPK2 and EVI5L interaction
- ^ GeneCards: NUDT18 (nucleoside diphosphate linked moiety X)-type motif 18 NUDT18 (nucleoside diphosphate linked moiety X)-type motif 18 Funtion
- ^ SRPK2 (serine/threonine-protein kinase 2) SRPK2 (serine/threonine-protein kinase 2) Funtion
- ^ D Jenkins, PL Beales, AOM Wilkie (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.
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: CS1 maint: multiple names: authors list (link)
Further reading
[edit]- Mitsunori Fukuda (June 2011). "TBC proteins: GAPs for mammalian small GTPase Rab?". Bioscience Reports. 31 (3). doi:10.1042/BSR20100112.
- S. B. Akopov, I. P. Chernov, T. Wahlström, M. B. Kostina, G. Klein, M. Henriksson, L. G. Nikolaev (January 2008). "Identification of recognition sites for Myc/Max/Mxd network proteins by a whole human chromosome 19 selection strategy". Biochemistry. 73 (11): 1260–1268. doi:10.1134/S0006297908110138.
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: CS1 maint: multiple names: authors list (link) - Huan-You Wang, Wen Lin, Jacqueline A. Dyck, Joanne M. Yeakley, Zhou Songyang, Lewis C. Cantley, and Xiang-Dong Fu (February 1998). "SRPK2: A Differentially Expressed SR Protein-specific Kinase Involved in Mediating the Interaction and Localization of Pre-mRNA Splicing Factors in Mammalian Cells". Journal of Cell Biology. 140 (4): 737–750. doi:10.1083/jcb.140.4.737.
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: CS1 maint: multiple names: authors list (link) - Tanja la Cour, Lars Kiemer, Anne Mølgaard, Ramneek Gupta, Karen Skriver and Søren Brunak (July 2004). "Analysis and prediction of leucine-rich nuclear export signals". Protein Engineering, Design & Selection. 17 (6): 527–536.
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: CS1 maint: multiple names: authors list (link) - Hiroyuki Sano, Lorena Eguez, Mary N. Teruel, Mitsunori Fukuda, Tuan D. Chuang, Jose A. Chavez, Gustav E. Lienhard, Timothy E. McGraw (April 2007). "Rab10, a Target of the AS160 Rab GAP, Is Required for Insulin-Stimulated Translocation of GLUT4 to the Adipocyte Plasma Membrane". Cell Metabolism. 5 (4): 293–303. doi:http://dx.doi.org/10.1016/j.cmet.2007.03.001.
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