Structural basis of O6-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein.

TitleStructural basis of O6-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein.
Publication TypeJournal Article
Year of Publication2010
AuthorsAramini, JM, Tubbs, JL, Kanugula, S, Rossi, P, Ertekin, A, Maglaqui, M, Hamilton, K, Ciccosanti, CT, Jiang, M, Xiao, R, Soong, T-T, Rost, B, Acton, TB, Everett, JK, Pegg, AE, Tainer, JA, Montelione, GT
JournalJ Biol Chem
Volume285
Issue18
Pagination13736-41
Date Published2010 Apr 30
ISSN1083-351X
KeywordsAlkyl and Aryl Transferases, Amino Acid Substitution, DNA, DNA Repair, Guanine, Humans, Mutation, Missense, Protein Folding, Vibrio parahaemolyticus
Abstract

Alkyltransferase-like proteins (ATLs) are a novel class of DNA repair proteins related to O(6)-alkylguanine-DNA alkyltransferases (AGTs) that tightly bind alkylated DNA and shunt the damaged DNA into the nucleotide excision repair pathway. Here, we present the first structure of a bacterial ATL, from Vibrio parahaemolyticus (vpAtl). We demonstrate that vpAtl adopts an AGT-like fold and that the protein is capable of tightly binding to O(6)-methylguanine-containing DNA and disrupting its repair by human AGT, a hallmark of ATLs. Mutation of highly conserved residues Tyr(23) and Arg(37) demonstrate their critical roles in a conserved mechanism of ATL binding to alkylated DNA. NMR relaxation data reveal a role for conformational plasticity in the guanine-lesion recognition cavity. Our results provide further evidence for the conserved role of ATLs in this primordial mechanism of DNA repair.

DOI10.1074/jbc.M109.093591
Alternate JournalJ. Biol. Chem.
PubMed ID20212037
PubMed Central IDPMC2859536
Grant ListCA018137 / CA / NCI NIH HHS / United States
CA097209 / CA / NCI NIH HHS / United States
R01 CA018137-35 / CA / NCI NIH HHS / United States
R01 CA018137-36 / CA / NCI NIH HHS / United States
U54-GM074958 / GM / NIGMS NIH HHS / United States