BEND2 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''BEND2''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. It is also found in other

vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...

s, including mammals, birds, and reptiles. The expression of BEND2 in ''

Homo sapiens Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...

'' is regulated and occurs at high levels in the skeletal muscle tissue of the male testis and in the

bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...

. The presence of the BEN domains in the BEND2 protein indicates that this protein may be involved in chromatin modification and regulation.

Gene

Common aliases

BEND2 stands for BEN domain containing 2 and is also known as CXorf20 (HGNC ID
28509
.

Locus and size

The locus for BEND2 is on the minus strand of the

X chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...

at Xp22.13. The gene is approximately 58 kilobases in length.

mRNA

Alternative splicing

BEND2 contains 14

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

s which undergo

alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...

to create five transcript variants that vary from 4,720 base pairs (bp) to 2,144 bp in the mature mRNA. The longest and most complete transcript of the gene, variant 1, encodes isoform 1 of the BEND2 protein (NP_699177.2).

5' and 3'UTR

The untranslated regions (UTR) flanking the

coding sequence The coding region of a gene, also known as the coding sequence (CDS), is the portion of a gene's DNA or RNA that codes for protein. Studying the length, composition, regulation, splicing, structures, and functions of coding regions compared to no ...

of BEND2 at the 5' and 3' end of the mature mRNA molecule contain sites for RNA-binding proteins, including RBMX,

pum2 Pumilio homolog 2 is an RNA-binding protein that in humans is encoded by the ''PUM2'' gene. Interactions PUM2 has been shown to interact with the following proteins: * CPEB * DAZL * DAZ1 Deleted in azoospermia 1, also known as DAZ1, is a protei ...

, and

EIF4B Eukaryotic translation initiation factor 4B is a protein that in humans is encoded by the ''EIF4B'' gene. Interactions eIF4B has been shown to interact with and stimulate the activity of eIF4A and bind to the eIF3 complex through the eIF3A subu ...

as well as microRNA binding sites. The

5'UTR The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of t ...

also contains an upstream in-frame stop codon and the 3'UTR contains a

polyadenylation Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euk ...

signal sequence.

Protein (Isoform 1)

Molecular weight and internal composition

The predicted

molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

is 87.9 kDal. The predicted

isoelectric point The isoelectric point (pI, pH(I), IEP), is the pH at which a molecule carries no net electrical charge or is electrically neutral in the statistical mean. The standard nomenclature to represent the isoelectric point is pH(I). However, pI is also u ...

is pH 5.07. The internal composition is enriched for

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

residues.

Isoforms

Corresponding to the five alternative transcripts of BEND2, the protein encoded by this gene is found in two

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

(1 and 2) as well as three predicted structures (X1, X2, and X3). These isoforms range from 813 to 645

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s in length. Isoform 1 is 799 amino acids in length.

Subcellular location

The presence of nuclear localization signals within the amino acid sequence or

primary structure Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthes ...

of the BEND2 protein leads to a prediction of

subcellular localization The cells of eukaryotic organisms are elaborately subdivided into functionally-distinct membrane-bound compartments. Some major constituents of eukaryotic cells are: extracellular space, plasma membrane, cytoplasm, nucleus, mitochondria, Golgi ap ...

in the nucleus. 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. BEND2 Diagram

Structure

The

secondary structure Protein secondary structure is the three dimensional conformational isomerism, form of ''local segments'' of proteins. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...

for BEND2 is unclear, in particular at the

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

, which is poorly conserved between orthologs. The

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

contains two BEN domains, which are predicted to form a series of alpha helices.

Post-translational modifications

Based on its primary structure, BEND2 is predicted to undergo N-terminus acetylation,

glycation Glycation (sometimes called non-enzymatic glycosylation) is the covalent attachment of a sugar to a protein or lipid. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic proces ...

of several lysine residues, SUMOlation, a SUMO interaction at the N-terminus, S-

palmitoylation Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (''S''-palmitoylation) and less frequently to serine and threonine (''O''-palmitoylation) residues of proteins, which are typically lipid bilayer, memb ...

, and extensive

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

Interacting Proteins

BEND2 is found to interact with the following proteins through experimental yeast two-hybrid screens or pull down assays. BEN domains of D

BEN Domains (protein feature)

BEND2 has two BEN domains at its C-terminus.

BEN domain In molecular biology, the BEN domain is a protein domain which is found in diverse proteins including: * SMAR1 (Scaffold/Matrix attachment region-binding protein 1; also known as BANP), a tumour-suppressor MAR-binding protein that down-regulates ...

s are found in a diverse array of proteins and are predicted to be important for

chromatin remodeling Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...

as well as for the recruitment of chromatin-modifying factors utilized during the process of

transcriptional regulation In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from alt ...

of gene expression. BEN domains are predicted to form four alpha helices that allow this domain to interact with its DNA target.
Dai et al. 2013
showed that the ''

Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...

'' 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.

Expression

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. The NCBI EST profile for this gene shows expression only in the testis and in the muscle.

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. Genomatix's MatInspector program predicted 418 transcription factor binding sites within the BEND2 promoter, including for SRY,

neurogenin Neurogenins are a family of bHLH transcription factors involved in specifying neuronal differentiation. It is one of many gene families related to the ''atonal'' gene in Drosophila. Other positive regulators of neuronal differentiation also exp ...

, interferon regulatory factor-3 (IRF-3), Ikaros2, and TCF/LEF-1.

Homology

Paralogs

The BEND2 protein has no known paralogs within the human genome.

BEN-domain containing gene family

The BEND2 gene belongs to a family of human genes known a
"BEN-domain containing”
This includes

BANP Protein BANP is a protein that can be found in humans, it is encoded by the ''BANP'' gene. It is a member of the human gene family, " BEN-domain containing", which includes eight other genes: BEND2, BEND3, BEND4, BEND5, BEND6, BEND7, NACC1 (BEND ...

(BEND1), BEND3, BEND4, BEND5, BEND6, BEND7, NACC1 (BEND8), and NACC2 (BEND9). The loci for these genes are spread throughout the human genome. 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

mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

bird Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweigh ...

crocodilia Crocodilia (or Crocodylia, both ) is an order of mostly large, predatory, semiaquatic reptiles, known as crocodilians. They first appeared 95 million years ago in the Late Cretaceous period ( Cenomanian stage) and are the closest living ...

, and

amphibian Amphibians are tetrapod, four-limbed and ectothermic vertebrates of the Class (biology), class Amphibia. All living amphibians belong to the group Lissamphibia. They inhabit a wide variety of habitats, with most species living within terres ...

s. The BEND2 protein has 42 known orthologs. The

of the protein, the location of its BEN domains, is highly conserved; however, the

is not well conserved, even within the order of

Primate Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians (monkeys and apes, the latter including huma ...

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 Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

, the transcription factors found in its

promoter region In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of i ...

, 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.

Clinical significance

The diseases that have been linked to BEND2 are related to the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

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 Chromosome 22 is one of the 23 pairs of chromosomes in human cell (biology), cells. Humans normally have two copies of chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 49 million DNA base pairs and ...

. * 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. * A young girl diagnosed with severe epileptic encephalopathy was found to have a 300-kb

deletion Deletion or delete may refer to: Computing * File deletion, a way of removing a file from a computer's file system * Code cleanup, a way of removing unnecessary variables, data structures, cookies, and temporary files in a programming language * ...

in a region that included BEND2, an extremely rare

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

not found in her parents’

genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...

s. * An individual with adult autism was identified to have a copy-number variant of unknown significance in a region only containing BEND2.

References

{{reflist Genes on human chromosome X