BEND2

{{Short description|Protein-coding gene in humans}} {{Infobox gene}} '''BEND2''' is a protein that in humans is encoded by the ''BEND2'' gene.<ref name=":1">{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/?term=CXorf20|title=BEND2 BEN domain containing 2 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2017-02-03}}</ref> It is also found in other vertebrates, including mammals, birds, and reptiles.<ref name=":1" /> The expression of BEND2 in ''Homo sapiens'' is regulated and occurs at high levels in the skeletal muscle tissue of the male testis and in the bone marrow.<ref name=":3">{{Cite web|url=https://www.ncbi.nlm.nih.gov/ieb/research/acembly/av.cgi?db=human&term=BEND2&submit=Go|title=AceView: Gene:BEND2, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView.|first1=Danielle|last1=Thierry-Mieg|first2=Jean|last2=Thierry-Mieg|website=www.ncbi.nlm.nih.gov|access-date=2017-02-03}}</ref><ref name=":0">{{Cite web|url=http://genatlas.medecine.univ-paris5.fr/fiche.php?n=34161|title=Genatlas sheet|website=genatlas.medecine.univ-paris5.fr|access-date=2017-02-03}}</ref><ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/UniGene/clust.cgi?UGID=218185&TAXID=9606&SEARCH=BEND2|archive-url=https://web.archive.org/web/20180817112242/https://www.ncbi.nlm.nih.gov/UniGene/clust.cgi?UGID=218185&TAXID=9606&SEARCH=BEND2|url-status=dead|archive-date=August 17, 2018|title=BEN domain containing 2 (BEND2)|website=www.ncbi.nlm.nih.gov|access-date=2017-02-03}}</ref> The presence of the BEN domains in the BEND2 protein indicates that this protein may be involved in chromatin modification and regulation.<ref name=":6" />

== Gene ==

=== Common aliases === BEND2 stands for BEN domain containing 2 and is also known as CXorf20 (HGNC ID: [https://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=28509 28509]).<ref name=":1" /><ref>{{Cite web|url=https://www.genenames.org/cgi-bin/gene_symbol_report?q=data/hgnc_data.php&hgnc_id=28509|title=BEND2 Symbol Report {{!}} HUGO Gene Nomenclature Committee|website=www.genenames.org|access-date=2017-02-03|archive-date=2015-03-26|archive-url=https://web.archive.org/web/20150326222606/http://www.genenames.org/cgi-bin/gene_symbol_report?q=data/hgnc_data.php&hgnc_id=28509|url-status=dead}}</ref><ref name=":2">{{Cite web|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=BEND2|title=BEND2 Gene|website=www.genecards.org|access-date=2017-02-03}}</ref>

=== Locus and size === The locus for BEND2 is on the minus strand of the X chromosome at Xp22.13. The gene is approximately 58 kilobases in length.<ref name=":1" />

== mRNA == [[File:BEND2 Alternative Transcripts.png|thumb|A screenshot of the NCBI Gene page for BEND2 showing alternative splicing of the BEND2 mRNA transcript.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/?term=CXorf20|title=BEND2 BEN domain containing 2 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2017-02-21}}</ref> Both exons (dark rectangles) and introns are shown. |500x500px]]

=== Alternative splicing === BEND2 contains 14 exons which undergo alternative splicing to create five transcript variants that vary from 4,720 base pairs (bp) to 2,144 bp in the mature mRNA.<ref name=":1" /><ref name=":2" /><ref name=":0" /> The longest and most complete transcript of the gene, variant 1, encodes isoform 1 of the BEND2 protein (NP_699177.2).<ref name=":1" />

=== 5' and 3'UTR === The untranslated regions (UTR) flanking the coding sequence of BEND2 at the 5' and 3' end of the mature mRNA molecule contain sites for RNA-binding proteins, including RBMX, pum2, and EIF4B as well as microRNA binding sites. The 5'UTR also contains an upstream in-frame stop codon and the 3'UTR contains a polyadenylation signal sequence.

== Protein (Isoform 1) == thumb|Annotated image of the tertiary and secondary structure of BEND2 based on I-TASSER prediction.<ref name="J Yang, R Yan 2015">{{cite journal | vauthors = Roy A, Kucukural A, Zhang Y | title = I-TASSER: a unified platform for automated protein structure and function prediction | journal = Nature Protocols | volume = 5 | issue = 4 | pages = 725–38 | date = April 2010 | pmid = 20360767 | pmc = 2849174 | doi = 10.1038/nprot.2010.5 }}</ref>|300x300px

=== Molecular weight and internal composition === The predicted molecular weight is 87.9 kDal.<ref name=":5">{{Cite web|url=http://workbench.sdsc.edu/|title=Statistical analysis of protein sequence (SAPS)|website=SDSC Biology Workbench- Protein Tools|access-date=4 April 2017}}</ref><ref>{{Cite web|url=http://workbench.sdsc.edu|title=AAStats|website=SDSC Biology Workbench- Protein Tools|access-date=4 April 2017}}</ref>

The predicted isoelectric point is pH 5.07.<ref>{{Cite web|url=http://workbench.sdsc.edu/|title=PI|website=SDSC Biology Workbench- Protein Tools|access-date=4 April 2017}}</ref>

The internal composition is enriched for serine residues.<ref name=":5" />

=== Isoforms === Corresponding to the five alternative transcripts of BEND2, the protein encoded by this gene is found in two isoforms (1 and 2) as well as three predicted structures (X1, X2, and X3). These isoforms range from 813 to 645 amino acids in length.<ref name=":1" /> Isoform 1 is 799 amino acids in length.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/protein/NP_699177.2|title=BEN domain-containing protein 2 isoform 1 [Homo sapiens] - Protein - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2017-02-03}}</ref>

=== Subcellular location === The presence of nuclear localization signals within the amino acid sequence or primary structure of the BEND2 protein leads to a prediction of subcellular localization in the nucleus.<ref name=":4">{{Cite web|url=http://www.genscript.com/psort.html|title=PSORT: Protein Subcellular Localization Prediction Too|date=24 November 1999|website=GenScript}}</ref> The pat7 [(P-X(1-3)-(3-4K/R)] signal and a nuclear bipartite signal are both found near the N-terminus of the protein.<ref name=":4" /><ref>{{cite journal | vauthors = Boisvert M, Bouchard-Lévesque V, Fernandes S, Tijssen P | title = Classic nuclear localization signals and a novel nuclear localization motif are required for nuclear transport of porcine parvovirus capsid proteins | journal = Journal of Virology | volume = 88 | issue = 20 | pages = 11748–59 | date = October 2014 | pmid = 25078698 | pmc = 4178750 | doi = 10.1128/JVI.01717-14 }}</ref> thumb|Post-translational modifications of BEND2. Grey diamonds indicate glycation and red diamonds show SUMOlation sites. N-terminus acetylation and SUMO interactions sites are marked at the front of the protein. Two nuclear localization signals at the same site near a domain of unknown function (Unk). |250x250px

=== Structure === The secondary structure for BEND2 is unclear, in particular at the N-terminus, which is poorly conserved between orthologs. The C-terminus contains two BEN domains, which are predicted to form a series of alpha helices.<ref name=":1" /><ref name=":6" />

=== Post-translational modifications === Based on its primary structure, BEND2 is predicted to undergo N-terminus acetylation, glycation of several lysine residues, SUMOlation, a SUMO interaction at the N-terminus, S-palmitoylation, and extensive phosphorylation.<ref>{{Cite web|url=https://www.expasy.org/proteomics/post-translational_modification|title=NetAcet, NetPhos, GPS, GPS-Lipids, GPS-SUMOylation, and NetGlycate|website=ExPASY}}</ref>

=== Interacting Proteins === BEND2 is found to interact with the following proteins through experimental yeast two-hybrid screens or pull down assays. {| class="wikitable" !Experiment type !Protein !Protein Function !Associated diseases |- |Two-hybrid screen |Ataxin 1(ATXN1)<ref>{{cite journal | vauthors = Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY | display-authors = 6 | title = A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration | journal = Cell | volume = 125 | issue = 4 | pages = 801–14 | date = May 2006 | pmid = 16713569 | doi = 10.1016/j.cell.2006.03.032 | s2cid = 13709685 | doi-access = free }}</ref> |Chromatin-binding factor; RNA metabolism |Spinocerebellar ataxia 1/spinocerebellar degeneration |- |Two-hybrid screen |Splicing factor 3A subunit 2(SF3A2)<ref name=":7">{{Cite web|url=http://www.ebi.ac.uk/intact/|title=IntAct- search for BEND2|website=EMBL-EBI|access-date=19 April 2017}}</ref> |Activation of U2 snRNP; microtubule-binding protein | |- |Two-hybrid screen |LIM Homeobox 2 (LHX2)<ref name=":7" /> |Transcriptional regulator for cell differentiation; sequence-specific DNA binding |Schizencephaly |- |Two-hybrid screen |Proline Rich 20D (PRR20D)<ref name=":7" /> |Unknown function | |- |Pull down assay |Amyolid precursor protein (APP)<ref>{{cite journal | vauthors = Oláh J, Vincze O, Virók D, Simon D, Bozsó Z, Tõkési N, Horváth I, Hlavanda E, Kovács J, Magyar A, Szũcs M, Orosz F, Penke B, Ovádi J | display-authors = 6 | title = Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein | journal = The Journal of Biological Chemistry | volume = 286 | issue = 39 | pages = 34088–100 | date = September 2011 | pmid = 21832049 | pmc = 3190826 | doi = 10.1074/jbc.M111.243907 | doi-access = free }}</ref> |Cell surface receptor in neurons; cleaved to form transcriptional activators |Cerebral amyloid angiopathy; Alzheimer's disease |} thumb|BEN domains of two D. melanogaster Insensitive proteins with their DNA target site.<ref name="J Yang, R Yan 2015"/>

== BEN Domains (protein feature) == BEND2 has two BEN domains at its C-terminus.<ref name=":1" /> BEN domains are found in a diverse array of proteins and are predicted to be important for chromatin remodeling as well as for the recruitment of chromatin-modifying factors utilized during the process of transcriptional regulation of gene expression.<ref name=":6">{{Cite web|url=https://www.ebi.ac.uk/interpro/entry/IPR018379|title=BEN domain (IPR018379) < InterPro < EMBL-EBI|website=www.ebi.ac.uk|language=en|access-date=2017-02-03}}</ref> BEN domains are predicted to form four alpha helices that allow this domain to interact with its DNA target.<ref name=":6" /><ref name=":8">{{cite journal | vauthors = Dai Q, Ren A, Westholm JO, Serganov AA, Patel DJ, Lai EC | title = The BEN domain is a novel sequence-specific DNA-binding domain conserved in neural transcriptional repressors | journal = Genes & Development | volume = 27 | issue = 6 | pages = 602–14 | date = March 2013 | pmid = 23468431 | pmc = 3613608 | doi = 10.1101/gad.213314.113 }}</ref>

[https://www.ncbi.nlm.nih.gov/pubmed/23468431 Dai et al. 2013] showed that the ''Drosophila melanogaster'' Insensitive (Insv) gene and corresponding protein has no domains of known chemical function yet it contains a single BEN domain. They illustrated the activity of the Insv protein in transcriptional regulation of genes and obtained a crystal structure of two Insv BEN domains interacting with their DNA target site.<ref name=":8" />

== Expression == thumb|NCBI GEO Profile GDS3113 / 227904 showing tissue expression data for BEND2.

=== Tissue expression pattern === The expression of the BEND2 gene is regulated and it is therefore not ubiquitously expressed in the human body. High expression occurs in the testis and in the bone marrow.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS3113:227904|title=GDS3113 / 227904|website=www.ncbi.nlm.nih.gov|access-date=2017-04-25}}</ref> The NCBI EST profile for this gene shows expression only in the testis and in the muscle.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/UniGene/ESTProfileViewer.cgi?uglist=Hs.403802|title=EST Profile - Hs.403802|last=National Center for Biotechnology Information|website=www.ncbi.nlm.nih.gov|access-date=2017-04-25}}{{dead link|date=July 2025|bot=medic}}{{cbignore|bot=medic}}</ref>

=== Transcriptional regulation of expression === The promoter regulating expression of BEND2 (GXP_2567556) is 1255 base pairs in length and is located directly upstream of the BEND2 gene. It regulates transcription of all five transcriptional variants of BEND2.<ref>{{Cite web|url=https://www.genomatix.de/|title=ElDorado: Annotation and Analysis|date=2017|website=Genomatix|access-date=2017-04-29|archive-date=2001-02-24|archive-url=https://web.archive.org/web/20010224072831/http://www.genomatix.de/|url-status=dead}}</ref> Genomatix's MatInspector program predicted 418 transcription factor binding sites within the BEND2 promoter, including for SRY, neurogenin, interferon regulatory factor-3 (IRF-3), Ikaros2, and TCF/LEF-1.

== Homology ==

=== Paralogs === The BEND2 protein has no known paralogs within the human genome.<ref>{{Cite web|url=https://genome.ucsc.edu/cgi-bin/hgBlat|title=Human genome, search for BEND2 isoform 1 protein|website=BLAT}}</ref>

=== BEN-domain containing gene family === The BEND2 gene belongs to a family of human genes known as [https://www.genenames.org/cgi-bin/genefamilies/set/422 "BEN-domain containing”]. This includes BANP (BEND1), BEND3, BEND4, BEND5, BEND6, BEND7, NACC1 (BEND8), and NACC2 (BEND9). The loci for these genes are spread throughout the human genome.<ref>{{Cite web|url=https://www.genenames.org/cgi-bin/genefamilies/set/422|title=BEN domain containing (BEND) Gene Family {{!}} HUGO Gene Nomenclature Committee|website=www.genenames.org|access-date=2017-02-21}}</ref> Each of these genes contains between one and four BEN domains. Except for at these motifs, the genes of the BEN family do not have similar sequences.

=== Orthologs === The BEND2 gene is conserved across evolutionary time as it has 114 known orthologs in a wide range of vertebrate species including mammals, birds, crocodilia, and amphibians.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/nuccore/NM_153346.4|title=Homo sapiens BEN domain containing 2 (BEND2), transcript variant 1, mR - Nucleotide - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2017-02-21}}</ref> The BEND2 protein has 42 known orthologs.<ref>{{Cite web|url=http://useast.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000177324;r=X:18162931-18220883|title=Gene: BEND2 (ENSG00000177324) - Summary - Homo sapiens - Ensembl genome browser 87|website=useast.ensembl.org|language=en-gb|access-date=2017-02-21}}</ref> The C-terminus of the protein, the location of its BEN domains, is highly conserved; however, the N-terminus is not well conserved, even within the order of Primates. {| class="wikitable sortable mw-collapsible" !Genus/species !Common name !Order !Date of divergence from ''H. sapiens'' (mya) !Accession number !Sequence length !Whole sequence identity !C-terminus identity |- |''Homo sapiens'' |Human |Primates |0 |NP_699177.2 |799 |1.000 |1.000 |- |''Pongo abelii'' |Orangutan |Primates |15.76 | -- |784 |0.921 |0.854 |- |''Macaca nemestrina'' |Southern pig-tailed macaque |Primates |29.44 |XP_011733709.1 |823 |0.694 |0.828 |- |''Vicugna pacos'' |Alpaca |Artiodactyla |96 |XP_015106214.1 |740 |0.433 |0.512 |- |''Ceratotherium simum simum'' |White rhinoceros |Perissodactyla |96 |XP_014646569.1 |864 |0.412 |0.527 |- |''Loxodonta africana'' |African bush elephant |Proboscidea |105 |XP_010594135.1 |829 |0.382 |0.489 |- |''Canis lupus familiaris'' |Dog |Carnivora |96 |XP_013967473.1 |900 |0.362 |0.445 |- |''Ailuropoda melanoleuca'' |Giant panada |Carnivora |96 |XP_019665441.1 |852 |0.353 |0.460 |- |''Rhinolophus sinicus'' |Chinese horseshoe bat |Chiroptera |96 |XP_019610944.1 |808 |0.345 |0.459 |- |''Dasypus novemcinctus'' |Nine-banded armadillo |Cingulata |105 |XP_012377569.1 |886 |0.342 |0.500 |- |''Trichechus manatus latirostris'' |Manatee |Sirenia |105 |XP_012412857.1 |950 |0.335 |0.475 |- |''Chrysochloris asiatica'' |Cape golden mole |Afrosoricida |105 |XP_006835746.1 |683 |0.330 |0.443 |- |''Oryctolagus cuniculus'' |European rabbit |Lagomorpha |90 |XP_017205124.1 |811 |0.305 |0.438 |- |''Monodelphis domestica'' |Gray short-tailed opossum |Didelphimorphia |159 |XP_007500895.1 |728 |0.303 |0.443 |- |''Ornithorhynchus anatinus'' |Platypus |Monotremata |177 |XP_007668655.1 |715 |0.302 |0.429 |- |''Gavialis gangeticus'' |Fish-eating crocodile |Crocodilia |312 |XP_019380828.1 |697 |0.309 |0.458 |- |''Chelonia mydas'' |Green sea turtle |Testudines |312 |XP_007070584.1 |749 |0.297 |0.453 |- |''Apteryx australis mantelli'' |North Island brown kiwi |Apterygiformes |312 |XP_013807123.1 |647 |0.295 |0.444 |- |''Columba livia'' |Rock dove |Columbiformes |312 |XP_005509980.1 |668 |0.287 |0.442 |- |''Pygoscelis adeliae'' |Adelie penguin |Sphenisciformes |312 |XP_009323754.1 |657 |0.282 |0.458 |- |''Nanorana parkeri'' |Tibet frog |Anura |352 |XP_018417228.1 |586 |0.260 |0.376 |}

== Function == BEND2 is predicted to be a DNA-binding protein due to the presence of BEN domains at its C-terminus, a hypothesis supported by its localization to the nucleus, the transcription factors found in its promoter region, and the nature of the proteins it interacts with. Though the precise function of the BEND2 protein is not yet well understood by the scientific community, BEN domains have been found to be important regulators of transcription.<ref name=":8" />

== Clinical significance == The diseases that have been linked to BEND2 are related to the central nervous system though expression of the gene is not highly observed in these tissues. * BEND2 was identified as one of the genes that causes a central nervous system primitive neuroectodermal tumor when fused with the MN1 gene, which is located on chromosome 22.<ref>{{Cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK374260/|title=PDQ Cancer Information Summaries|last=PDQ Pediatric Treatment Editorial Board|date=2002-01-01|publisher=National Cancer Institute (US)|location=Bethesda (MD)|pmid=27466641|chapter=Childhood Cancer Genomics (PDQ®): Health Professional Version}}</ref><ref>{{cite journal | vauthors = Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DT, Capper D, Sill M, Buchhalter I, Northcott PA, Leis I, Ryzhova M, Koelsche C, Pfaff E, Allen SJ, Balasubramanian G, Worst BC, Pajtler KW, Brabetz S, Johann PD, Sahm F, Reimand J, Mackay A, Carvalho DM, Remke M, Phillips JJ, Perry A, Cowdrey C, Drissi R, Fouladi M, Giangaspero F, Łastowska M, Grajkowska W, Scheurlen W, Pietsch T, Hagel C, Gojo J, Lötsch D, Berger W, Slavc I, Haberler C, Jouvet A, Holm S, Hofer S, Prinz M, Keohane C, Fried I, Mawrin C, Scheie D, Mobley BC, Schniederjan MJ, Santi M, Buccoliero AM, Dahiya S, Kramm CM, von Bueren AO, von Hoff K, Rutkowski S, Herold-Mende C, Frühwald MC, Milde T, Hasselblatt M, Wesseling P, Rößler J, Schüller U, Ebinger M, Schittenhelm J, Frank S, Grobholz R, Vajtai I, Hans V, Schneppenheim R, Zitterbart K, Collins VP, Aronica E, Varlet P, Puget S, Dufour C, Grill J, Figarella-Branger D, Wolter M, Schuhmann MU, Shalaby T, Grotzer M, van Meter T, Monoranu CM, Felsberg J, Reifenberger G, Snuderl M, Forrester LA, Koster J, Versteeg R, Volckmann R, van Sluis P, Wolf S, Mikkelsen T, Gajjar A, Aldape K, Moore AS, Taylor MD, Jones C, Jabado N, Karajannis MA, Eils R, Schlesner M, Lichter P, von Deimling A, Pfister SM, Ellison DW, Korshunov A, Kool M | display-authors = 6 | title = New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs | language = English | journal = Cell | volume = 164 | issue = 5 | pages = 1060–1072 | date = February 2016 | pmid = 26919435 | pmc = 5139621 | doi = 10.1016/j.cell.2016.01.015 }}</ref> * A rare primary central nervous system lymphoma tumor was found to have a high mutation ratio for BEND2; however, the authors do not describe this gene as primarily responsible for the tumor.<ref>{{cite journal | vauthors = Fukumura K, Kawazu M, Kojima S, Ueno T, Sai E, Soda M, Ueda H, Yasuda T, Yamaguchi H, Lee J, Shishido-Hara Y, Sasaki A, Shirahata M, Mishima K, Ichimura K, Mukasa A, Narita Y, Saito N, Aburatani H, Nishikawa R, Nagane M, Mano H | display-authors = 6 | title = Genomic characterization of primary central nervous system lymphoma | journal = Acta Neuropathologica | volume = 131 | issue = 6 | pages = 865–75 | date = June 2016 | pmid = 26757737 | doi = 10.1007/s00401-016-1536-2 | s2cid = 928277 }}</ref> * A young girl diagnosed with severe epileptic encephalopathy was found to have a 300-kb deletion in a region that included BEND2, an extremely rare mutation not found in her parents’ genomes.<ref>{{cite journal | vauthors = Bahi-Buisson N, Girard B, Gautier A, Nectoux J, Fichou Y, Saillour Y, Poirier K, Chelly J, Bienvenu T | display-authors = 6 | title = Epileptic encephalopathy in a girl with an interstitial deletion of Xp22 comprising promoter and exon 1 of the CDKL5 gene | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 153B | issue = 1 | pages = 202–7 | date = January 2010 | pmid = 19455595 | doi = 10.1002/ajmg.b.30974 | s2cid = 8211913 }}</ref> * An individual with adult autism was identified to have a copy-number variant of unknown significance in a region only containing BEND2.<ref>{{cite journal | vauthors = Stobbe G, Liu Y, Wu R, Hudgings LH, Thompson O, Hisama FM | title = Diagnostic yield of array comparative genomic hybridization in adults with autism spectrum disorders | journal = Genetics in Medicine | volume = 16 | issue = 1 | pages = 70–7 | date = January 2014 | pmid = 23765050 | doi = 10.1038/gim.2013.78 | doi-access = free }}</ref>

== References == {{reflist}}

Category:Genes on human chromosome X