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 phys ...
binds to
DNA that contains one or more symmetrically
methylated 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 and
chromosome X 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, res ...
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
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, res ...
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
* ...
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. 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 proteins, which recruit a variety of
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 hi ...
(HDAC) complexes and
chromatin
Chromatin is a complex of DNA and protein found in eukaryote, 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 ...
remodelling factors, leading to chromatin compaction and, consequently, to
transcriptional
Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...
repression. The MBD of MeCP2,
MBD1,
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 a ...
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, cultu ...
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, the MBD has been shown to mediate
protein-protein interactions.
MBDs are also found in DNA
demethylase.
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 a ...
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 helic ...
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, 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 ge ...
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, ...
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