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

J Biol Chem. 2010 Apr 30;285(18):13736-41. doi: 10.1074/jbc.M109.093591. Epub 2010 Mar 8.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alkyl and Aryl Transferases / chemistry*
  • Alkyl and Aryl Transferases / genetics
  • Alkyl and Aryl Transferases / metabolism
  • Amino Acid Substitution
  • DNA / chemistry*
  • DNA / genetics
  • DNA / metabolism
  • DNA Repair / physiology*
  • Guanine / analogs & derivatives*
  • Guanine / chemistry
  • Guanine / metabolism
  • Humans
  • Mutation, Missense
  • Protein Folding*
  • Vibrio parahaemolyticus / enzymology*
  • Vibrio parahaemolyticus / genetics

Substances

  • Guanine
  • DNA
  • O-(6)-methylguanine
  • Alkyl and Aryl Transferases