Structural basis of O6-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein.
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.
Aramini
James M
JM
Center for Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA. jma@cabm.rutgers.edu
Tubbs
Julie L
JL
Kanugula
Sreenivas
S
Rossi
Paolo
P
Ertekin
Asli
A
Maglaqui
Melissa
M
Hamilton
Keith
K
Ciccosanti
Colleen T
CT
Jiang
Mei
M
Xiao
Rong
R
Soong
Ta-Tsen
TT
Rost
Burkhard
B
Acton
Thomas B
TB
Everett
John K
JK
Pegg
Anthony E
AE
Tainer
John A
JA
Montelione
Gaetano T
GT
D019883:Alkyl and Aryl Transferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D017510:Protein Folding; D014736:Vibrio parahaemolyticus / Q000201:enzymology* / Q000235:genetics
D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine; D019883:Alkyl and Aryl Transferases