CTBP2
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C-terminal-binding protein 2 also known as CtBP2 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 ''CTBP2''
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 ...
.


Function

The CtBPs -
CtBP1 C-terminal-binding protein 1 also known as CtBP1 is a protein that in humans is encoded by the ''CTBP1'' gene. CtBP1 is one of two CtBP proteins, the other protein being CtBP2. Function The CtBP1 protein was originally identified as a human prote ...
and CtBP2 in mammals - are among the best characterized transcriptional
corepressor In the field of molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, b ...
s. They typically turn their target genes off. They do this by binding to sequence-specific DNA-binding proteins that carry a short motif of the general form Proline-Isoleucine-Aspartate-Leucine-Serine (the PIDLS motif). They then recruit histone modifying enzymes,
histone deacetylase Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
s, histone
methylase Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossm ...
s and histone
demethylase Demethylases are enzymes that remove methyl (CH3) groups from nucleic acids, proteins (particularly histones), and other molecules. Demethylases are important epigenetic proteins, as they are responsible for transcriptional regulation of the genom ...
s. These enzymes are thought to work together to remove activating and add repressive histone marks. For example, histone deacetylase 1 (
HDAC1 Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene. Function Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. T ...
) and
HDAC2 Histone deacetylase 2 (HDAC2) is an enzyme that in humans is encoded by the ''HDAC2'' gene. It belongs to the histone deacetylase class of enzymes responsible for the removal of acetyl groups from lysine residues at the N-terminal region of the co ...
can remove the activating mark histone 3 acetyl lysine 9 (H3K9Ac), then the histone methylase
G9a Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a, is a histone methyltransferase enzyme that in humans is encoded by the ''EHMT2'' gene. G9a catalyzes the mono- and di-methylated states of histone H3 at lysine residue 9 ...
can add methyl groups, while the histone demethylase lysine specific demethylase 1 (
LSD1 Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein in humans that is encoded by the KDM1A gene. LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-me ...
) can remove the activating mark H3K4me. The CtBPs bind to many different DNA-binding proteins and also bind to co-repressors that are themselves bound to DNA-binding proteins, such as Friend of GATA (
Fog Fog is a visible aerosol consisting of tiny water droplets or ice crystals suspended in the air at or near the Earth's surface. Reprint from Fog can be considered a type of low-lying cloud usually resembling stratus, and is heavily influ ...
). CtBPs can also dimerize and multimerize to bridge larger transcriptional complexes. They appear to be primarily scaffold proteins that allow the assembly of gene repression complexes. One interesting aspect of CtBPs is their ability to bind to
NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
and to a lesser extent NAD+. It has been proposed that this will enable them to sense the metabolic status of the cell and to regulate genes in response to changes in the NADH/NAD+ ratio. Accordingly, CtBPs have been found to be important in fat biology, binding to key proteins such as
PRDM16 PR domain containing 16, also known as PRDM16, is a protein which in humans is encoded by the ''PRDM16'' gene. PRDM16 acts as a transcription coregulator that controls the development of brown adipocytes in brown adipose tissue. Previously, thi ...
, NRIP, and FOG2. The full functional roles of CtBP proteins in mammals have been difficult to evaluate because of partial redundancy between CtBP1 and CtBP2. Similarly, the early lethality of the CtBP2 knockout and of double knockout mice has precluded detailed analysis of the cellular effects of deleting these proteins. Important results have emerged from model organisms where there is only a single CtBP gene. In ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
'' CtBP is involved in development and in
circadian rhythm A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...
s. In the worm ''
C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...
'' CtBP is involved in life span. Both circadian rhythms and life span appear to be linked to metabolism supporting the role for CtBPs in metabolic sensing. The mammalian CtBP2 gene produces alternative transcripts encoding two distinct proteins. In addition to the transcriptional repressor (
corepressor In the field of molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, b ...
) discussed above, there is a longer isoform that is a major component of specialized synapses known as synaptic ribbons. Both proteins contain a NAD+ binding domain similar to NAD+-dependent 2-hydroxyacid dehydrogenases. A portion of the
3'-untranslated region In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...
was used to map this gene to chromosome 21q21.3; however, it was noted that similar loci elsewhere in the genome are likely. Blast analysis shows that this gene is present on chromosome 10.


Alternative Promoter Usage

In the vertebrate
retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
, the CtBP2 gene is transcribed from alternative promoters during retinal development yielding the CTBP2 transcriptional coregulator as well as the larger ribbon synapse scaffolding protein RIBEYE. The multi use functionality of the CtBP2 locus appears to be conserved between avian and primate retinae with production of the RIBEYE mRNA being developmentally delayed by an
epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
silencing mechanism. In the developing human retina, transcription of the RIBEYE mRNA isoform is epigenetically regulated by
DNA methylation DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts t ...
. DNA sequences comprising the proximal RIBEYE promoter are enriched for DNA methylation and delay transcription of this isoform, possibly by inhibiting binding of the Cone-rod homeobox (CRX) transcription factor. Global transcript analysis of human pluripotent stem cell (hPSC)-derived 3D retinal
organoids An organoid is a miniaturized and simplified version of an organ produced in vitro in three dimensions that shows realistic micro-anatomy. They are derived from one or a few cells from a tissue, embryonic stem cells or induced pluripotent stem ...
demonstrates early and persistent expression of the CTPB2 isoform followed by delayed RIBEYE expression in the developing human eye.


Interactions

CTBP2 has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with: *
FHL3 Four and a half LIM domains protein 3 is a protein that in humans is encoded by the ''FHL3'' gene. LIM proteins are defined by the possession of a highly conserved double zinc finger motif called the LIM domain. upplied by OMIMref name="entrez"/ ...
, *
KLF3 Krüppel-like factor 3 is a protein that in humans is encoded by the ''KLF3'' gene. Structure KLF3, originally termed Basic Krüppel-like Factor (BKLF), was the third member of the Krüppel-like factor family of zinc finger transcription fact ...
, *
KLF8 Krueppel-like factor 8 is a protein that in humans is encoded by the ''KLF8'' gene. KLF8 belongs to the family of KLF protein. KLF8 is activated by KLF1 along with KLF3 while KLF3 represses KLF8. Interactions KLF8 has been shown to interact wi ...
, * Mdm2, *
NRIP1 Nuclear receptor-interacting protein 1 (NRIP1) also known as receptor-interacting protein 140 (RIP140) is a protein that in humans is encoded by the ''NRIP1'' gene. Function Nuclear receptor interacting protein 1 (NRIP1) is a nuclear prote ...
, *
SOX6 Transcription factor SOX-6 is a protein that in humans is encoded by the ''SOX6'' gene. Function The SOX gene family encodes a group of transcription factors defined by the conserved high mobility group (HMG) DNA-binding domain. Unlike most tr ...
, and *
ZFPM2 Zinc finger protein ZFPM2, i.e. zinc finger protein, FOG family member 2, but also termed ''Friend of GATA2, Friend of GATA-2, FOG2'', or ''FOG-2'', is a protein that in humans is encoded by the ''ZFPM2'' and in mice by the ''Zfpm2'' gene. The zi ...
.


References


Further reading

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External links

* * {{Transcription coregulators Transcription coregulators