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The AID/APOBEC family of nucleic acid mutators.

Conticello SG - Genome Biol. (2008)

Bottom Line: The AID/APOBECs, a group of cytidine deaminases, represent a somewhat unusual protein family that can insert mutations in DNA and RNA as a result of their ability to deaminate cytidine to uridine.APOBEC1 edits the mRNA for apolipoprotein B, a protein involved in lipid transport.A detailed understanding of the biological roles of the family is still some way off, however, and the functions of some members of the family are completely unknown.

View Article: PubMed Central - HTML - PubMed

Affiliation: Core Research Laboratory, Istituto Toscano Tumori, Florence, Via Cosimo il Vecchio 2, 50139 Firenze, Italy. silvo.conticello@ittumori.it

ABSTRACT
The AID/APOBECs, a group of cytidine deaminases, represent a somewhat unusual protein family that can insert mutations in DNA and RNA as a result of their ability to deaminate cytidine to uridine. The ancestral AID/APOBECs originated from a branch of the zinc-dependent deaminase superfamily at the beginning of the vertebrate radiation. Other members of the family have arisen in mammals and present a history of complex gene duplications and positive selection. All AID/APOBECs have a characteristic zinc-coordination motif, which forms the core of the catalytic site. The crystal structure of human APOBEC2 shows remarkable similarities to that of the bacterial tRNA-editing enzyme TadA, which suggests a conserved mechanism by which polynucleotides are recognized and deaminated. The AID/APOBECs seem to have diverse roles. AID and the APOBEC3s are DNA mutators, acting in antigen-driven antibody diversification processes and in an innate defense system against retroviruses, respectively. APOBEC1 edits the mRNA for apolipoprotein B, a protein involved in lipid transport. A detailed understanding of the biological roles of the family is still some way off, however, and the functions of some members of the family are completely unknown. Given their ability to mutate DNA, a role for the AID/APOBECs in the onset of cancer has been proposed.

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Three-dimensional structure of APOBEC2 [20]. α Helices 2 and 3, which hold the histidine and the cysteines forming the catalytic pocket, are indicated in blue. The zinc atom is indicated as a yellow sphere, the residues coordinating the zinc atom are colored in red, and the glutamate acting as proton donor in purple (beneath the zinc atom). The β strands providing the molecule's scaffold are indicated in bright green. The loops that might play a role in substrate recognition are indicated: the loop conserved in TadA [21] is in orange and the SSS loop is in pink. PDB: 2NYT.
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Figure 4: Three-dimensional structure of APOBEC2 [20]. α Helices 2 and 3, which hold the histidine and the cysteines forming the catalytic pocket, are indicated in blue. The zinc atom is indicated as a yellow sphere, the residues coordinating the zinc atom are colored in red, and the glutamate acting as proton donor in purple (beneath the zinc atom). The β strands providing the molecule's scaffold are indicated in bright green. The loops that might play a role in substrate recognition are indicated: the loop conserved in TadA [21] is in orange and the SSS loop is in pink. PDB: 2NYT.

Mentions: Like all zinc-dependent deaminases, the main structural feature of the AID/APOBECs is the domain responsible for their catalytic activity. In the amino-acid sequence, the signature for this domain is a H [AV]E-x[24-36]-PCxxC motif (where x is any amino acid) (Figure 3). The histidine (H) and the two cysteines (C) coordinate a zinc atom and form the catalytic core of the deaminase (Figure 4). The cytidine is bound in this pocket and is deaminated through nucleophilic attack on the ammonium group on its carbon 4 by an activated water molecule (coordinated by the zinc atom) and the nearby glutamate, which acts as a proton donor.


The AID/APOBEC family of nucleic acid mutators.

Conticello SG - Genome Biol. (2008)

Three-dimensional structure of APOBEC2 [20]. α Helices 2 and 3, which hold the histidine and the cysteines forming the catalytic pocket, are indicated in blue. The zinc atom is indicated as a yellow sphere, the residues coordinating the zinc atom are colored in red, and the glutamate acting as proton donor in purple (beneath the zinc atom). The β strands providing the molecule's scaffold are indicated in bright green. The loops that might play a role in substrate recognition are indicated: the loop conserved in TadA [21] is in orange and the SSS loop is in pink. PDB: 2NYT.
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Related In: Results  -  Collection

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Figure 4: Three-dimensional structure of APOBEC2 [20]. α Helices 2 and 3, which hold the histidine and the cysteines forming the catalytic pocket, are indicated in blue. The zinc atom is indicated as a yellow sphere, the residues coordinating the zinc atom are colored in red, and the glutamate acting as proton donor in purple (beneath the zinc atom). The β strands providing the molecule's scaffold are indicated in bright green. The loops that might play a role in substrate recognition are indicated: the loop conserved in TadA [21] is in orange and the SSS loop is in pink. PDB: 2NYT.
Mentions: Like all zinc-dependent deaminases, the main structural feature of the AID/APOBECs is the domain responsible for their catalytic activity. In the amino-acid sequence, the signature for this domain is a H [AV]E-x[24-36]-PCxxC motif (where x is any amino acid) (Figure 3). The histidine (H) and the two cysteines (C) coordinate a zinc atom and form the catalytic core of the deaminase (Figure 4). The cytidine is bound in this pocket and is deaminated through nucleophilic attack on the ammonium group on its carbon 4 by an activated water molecule (coordinated by the zinc atom) and the nearby glutamate, which acts as a proton donor.

Bottom Line: The AID/APOBECs, a group of cytidine deaminases, represent a somewhat unusual protein family that can insert mutations in DNA and RNA as a result of their ability to deaminate cytidine to uridine.APOBEC1 edits the mRNA for apolipoprotein B, a protein involved in lipid transport.A detailed understanding of the biological roles of the family is still some way off, however, and the functions of some members of the family are completely unknown.

View Article: PubMed Central - HTML - PubMed

Affiliation: Core Research Laboratory, Istituto Toscano Tumori, Florence, Via Cosimo il Vecchio 2, 50139 Firenze, Italy. silvo.conticello@ittumori.it

ABSTRACT
The AID/APOBECs, a group of cytidine deaminases, represent a somewhat unusual protein family that can insert mutations in DNA and RNA as a result of their ability to deaminate cytidine to uridine. The ancestral AID/APOBECs originated from a branch of the zinc-dependent deaminase superfamily at the beginning of the vertebrate radiation. Other members of the family have arisen in mammals and present a history of complex gene duplications and positive selection. All AID/APOBECs have a characteristic zinc-coordination motif, which forms the core of the catalytic site. The crystal structure of human APOBEC2 shows remarkable similarities to that of the bacterial tRNA-editing enzyme TadA, which suggests a conserved mechanism by which polynucleotides are recognized and deaminated. The AID/APOBECs seem to have diverse roles. AID and the APOBEC3s are DNA mutators, acting in antigen-driven antibody diversification processes and in an innate defense system against retroviruses, respectively. APOBEC1 edits the mRNA for apolipoprotein B, a protein involved in lipid transport. A detailed understanding of the biological roles of the family is still some way off, however, and the functions of some members of the family are completely unknown. Given their ability to mutate DNA, a role for the AID/APOBECs in the onset of cancer has been proposed.

Show MeSH
Related in: MedlinePlus