The Methyl-CpG-binding domain (MBD) in

molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...

binds to DNA that contains one or more symmetrically

methylated In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...

CpGs. MBD has negligible non-specific affinity for unmethylated DNA. In vitro foot-printing with the chromosomal protein

MeCP2 ''MECP2'' (methyl CpG binding protein 2) is a gene that encodes the protein MECP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in ...

showed that the MBD could protect a 12 nucleotide region surrounding a methyl CpG pair. DNA methylation at CpG dinucleotides, the most common DNA modification in eukaryotes, has been associated with various phenomena such as alterations in chromatin structure,

genomic Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dim ...

imprinting,

transposon A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transpo ...

and

chromosome X 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 ...

inactivation, differentiation, and

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. Effects of DNA methylation are mediated through

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 ...

s that

bind BIND () is a suite of software for interacting with the Domain Name System (DNS). Its most prominent component, named (pronounced ''name-dee'': , short for ''name daemon''), performs both of the main DNS server roles, acting as an authoritative ...

to symmetrically methylated CpGs. Such

s contain a specific

domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a partial function **Domain of holomorphy of a function * Do ...

of ~70 residues, the methyl-CpG-binding domain (MBD), which is linked to additional domains associated with chromatin, such as the

bromodomain A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the ''N''-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducin ...

, the

AT hook The second AT-hook of HMGA1 (black ribbon) bound to the minor-groove of AT-rich DNA. The amino-acid side chains and nucleotides have been hidden. The AT-hook is a DNA-binding motif present in many proteins, including the high mobility group (H ...

motif, the

SET domain Set, The Set, SET or SETS may refer to: Science, technology, and mathematics Mathematics *Set (mathematics), a collection of elements * Category of sets, the category whose objects and morphisms are sets and total functions, respectively Electr ...

, or the

PHD finger PHD or PhD may refer to: * Doctor of Philosophy (PhD), an academic qualification Entertainment * '' PhD: Phantasy Degree'', a Korean comic series * ''Piled Higher and Deeper'', a web comic * Ph.D. (band), a 1980s British group ** Ph.D. (Ph.D. albu ...

. MBD-containing

proteins 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 ...

appear to act as

structural A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such ...

proteins, which recruit a variety of histone deacetylase (HDAC) complexes and

chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...

remodelling factors, leading to chromatin compaction and, consequently, to transcriptional repression. The MBD of MeCP2,

MBD1 Methyl-CpG-binding domain protein 1 is a protein that in humans is encoded by the ''MBD1'' gene. The protein encoded by MBD1 binds to methylated sequences in DNA, and thereby influences transcription. It binds to a variety of methylated sequence ...

MBD2 Methyl-CpG-binding domain protein 2 is a protein that in humans is encoded by the ''MBD2'' gene. Function DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP ...

MBD4 Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the ''MBD4'' gene. Structure Human MBD4 protein has 580 amino acids with a methyl-CpG-binding domain at amino acids 82–147 and a C-terminal DNA glycosylase domain at ...

and BAZ2 mediates binding to DNA, and in cases of MeCP2, MBD1 and MBD2, preferentially to methylated CpG. In

human 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, ...

MBD3 Methyl-CpG-binding domain protein 3 is a protein that in humans is encoded by the ''MBD3'' gene. Function DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins ME ...

and

SETDB1 Histone-lysine N-methyltransferase SETDB1 is an enzyme that in humans is encoded by the ''SETDB1'' gene. SETDB1 is also known as KMT1E or H3K9 methyltransferase ESET. Function The SET domain is a highly conserved, approximately 150-amino acid ...

, the MBD has been shown to mediate protein-protein interactions. MBDs are also found in DNA

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 ...

. The MBD folds into an alpha/beta sandwich

structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

comprising a layer of twisted beta sheet, backed by another layer formed by the alpha1

helix A helix () is a shape like a corkscrew or spiral staircase. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is formed as two intertwined helices, ...

and a hairpin

loop Loop or LOOP may refer to: Brands and enterprises * Loop (mobile), a Bulgarian virtual network operator and co-founder of Loop Live * Loop, clothing, a company founded by Carlos Vasquez in the 1990s and worn by Digable Planets * Loop Mobile, an ...

at the C terminus. These layers are both

amphipathic An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compoun ...

, with the alpha1 helix and the

beta sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a g ...

lying parallel and the

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...

faces tightly packed against each other. The beta sheet is composed of two long inner strands (beta2 and beta3) sandwiched by two shorter outer strands (beta1 and beta4). The structure of the MBD domain bound to methylated DNA has been solved (). It recognizes the hydration of the major groove at methylated sites.

References

{{InterPro content, IPR001739 Protein domains