In molecular biology, the Macro domain (often also written macrodomain) or A1pp domain is a module of about 180

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 ...

s which can bind

ADP-ribose Adenosine diphosphate ribose (ADPR) is an ester molecule formed into chains by the enzyme poly ADP ribose polymerase. ADPR is created from cyclic ADP-ribose (cADPR) by the CD38 enzyme using nicotinamide adenine dinucleotide (NAD+) as a cofactor. ...

, an NAD

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

, or related ligands. Binding to ADP-ribose can be either

covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...

non-covalent In chemistry, a non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. The ...

: in certain cases it is believed to bind non-covalently, while in other cases (such as

Aprataxin Aprataxin is a protein that in humans is encoded by the ''APTX'' gene. This gene encodes a member of the histidine triad (HIT) superfamily, some of which have nucleotide-binding and diadenosine polyphosphate hydrolase activities. The encoded pro ...

) it appears to bind both non-covalently through a

zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...

motif, and covalently through a separate region of the

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, respon ...

Function

The domain was described originally in association with the ADP-ribose 1''-phosphate (Appr-1''-P)-processing activity (A1pp) of the

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to consti ...

YBR022W protein and called A1pp. However, the domain has been renamed Macro as it is the C-terminal domain of

mammalia 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), fu ...

n core histone macro-H2A. Macro domain

s can be found in

eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...

s, in (mostly pathogenic) bacteria, in archaea and in ssRNA viruses, such as coronaviruses,

Rubella Rubella, also known as German measles or three-day measles, is an infection caused by the rubella virus. This disease is often mild, with half of people not realizing that they are infected. A rash may start around two weeks after exposure and ...

and

Hepatitis E virus The hepatitis E virus (HEV) is the causative agent of hepatitis E. It is of the species ''Orthohepevirus A.'' Globally, approximately 939 million corresponding to 1 in 8 individuals have ever experienced HEV infection. About 15–110 million in ...

es. In

vertebrates 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, wi ...

the domain occurs in e.g. histone macroH2A, predicted poly-ADP-ribose polymerases (PARPs) and B aggressive lymphoma (BAL) protein.

ADP-ribosylation ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosi ...

of proteins is an important

post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribos ...

that occurs in a variety of biological processes, including

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

, regulation of

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

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 ...

biology, maintenance of

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 ...

stability,

telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mo ...

dynamics,

cell differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...

and proliferation,

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dig ...

and apoptosis, and long-term memory formation. The Macro domain recognises the ADP-ribose nucleotide and in some cases poly-ADP-ribose, and is thus a high-affinity ADP-ribose-binding module found in a number of otherwise unrelated proteins. ADP-ribosylation of DNA is relatively uncommon and has only been described for a small number of

toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...

s that include pierisin, scabin and DarT. The Macro domain from the antitoxin DarG of the

toxin-antitoxin system A toxin-antitoxin system is a set of two or more closely linked genes that together encode both a "toxin" protein and a corresponding "antitoxin". Toxin-antitoxin systems are widely distributed in prokaryotes, and organisms often have them in mul ...

DarTG, both binds and removes the ADP-ribose modification added to DNA by the toxin DarT. The Macro domain from

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, ...

, macroH2A1.1, binds an NAD metabolite ''O''-acetyl-ADP-ribose.

Structure

The 3D structure of the Macro domain describes a mixed alpha/beta fold of a mixed

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 gen ...

sandwiched between four

helices 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 helice ...

with the ligand-binding pocket lies within the fold. Several Macro domain-only domains are shorter than the structure of AF1521 and lack either the first strand or the C-terminal

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 hel ...

5. Well conserved

residues Residue may refer to: Chemistry and biology * An amino acid, within a peptide chain * Crop residue, materials left after agricultural processes * Pesticide residue, refers to the pesticides that may remain on or in food after they are appli ...

form a

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, ...

cleft and cluster around the AF1521-ADP-ribose

binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may inclu ...

References

{{InterPro content, IPR002589 Protein domains

Function

Structure

See also

References