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The C-terminal domain of the adenine-DNA glycosylase MutY confers specificity for 8-oxoguanine.adenine mispairs and may have evolved from MutT, an 8-oxo-dGTPase.

Publication ,  Journal Article
Noll, DM; Gogos, A; Granek, JA; Clarke, ND
Published in: Biochemistry
May 18, 1999

MutY is an adenine-DNA glycosylase with specificity for mismatches involving 8-oxoguanine (oG.A) or guanine (G.A). In addition to a 25 kDa catalytic domain common to all members of its DNA glycosylase superfamily, MutY has a 14 kDa C-terminal domain. Sequence analyses suggest that this C-terminal domain is distantly related to MutT, a pyrophosphohydrolase specific for 2'-deoxy-8-oxoguanosine triphosphate (doGTP). Here we present biochemical evidence that the MutT-like domain of MutY is the principal determinant of oG specificity. First, MutY dissociates approximately 1500-fold more slowly from oG-containing product DNA than from G-containing product, but a truncated protein lacking the C-terminal domain dissociates as rapidly from oG-DNA as the full-length protein dissociates from G-DNA. Second, MutY removes adenine from oG.A mismatches almost 30-fold faster than from G.A mismatches in a pre-steady-state assay, but deletion of the C-terminal domain reduces this specificity for oG.A to less than 4-fold. The kinetic data are consistent with a model in which binding of oG to the C-terminal domain of MutY accelerates the pre-steady-state glycosylase reaction by facilitating adenine base flipping. The observation that oG specificity derives almost exclusively from the C-terminal domain of MutY adds credence to the sequence analyses and suggests that specificity for oG.A mismatches was acquired by fusion of a MutT-like protein onto the core catalytic domain of an adenine-DNA glycosylase.

Duke Scholars

Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

May 18, 1999

Volume

38

Issue

20

Start / End Page

6374 / 6379

Location

United States

Related Subject Headings

  • Sequence Homology, Amino Acid
  • Sequence Analysis
  • Protein Structure, Tertiary
  • Peptide Fragments
  • N-Glycosyl Hydrolases
  • Molecular Sequence Data
  • Kinetics
  • Humans
  • Guanine
  • Escherichia coli
 

Citation

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Noll, D. M., Gogos, A., Granek, J. A., & Clarke, N. D. (1999). The C-terminal domain of the adenine-DNA glycosylase MutY confers specificity for 8-oxoguanine.adenine mispairs and may have evolved from MutT, an 8-oxo-dGTPase. Biochemistry, 38(20), 6374–6379. https://doi.org/10.1021/bi990335x
Noll, D. M., A. Gogos, J. A. Granek, and N. D. Clarke. “The C-terminal domain of the adenine-DNA glycosylase MutY confers specificity for 8-oxoguanine.adenine mispairs and may have evolved from MutT, an 8-oxo-dGTPase.Biochemistry 38, no. 20 (May 18, 1999): 6374–79. https://doi.org/10.1021/bi990335x.
Noll, D. M., et al. “The C-terminal domain of the adenine-DNA glycosylase MutY confers specificity for 8-oxoguanine.adenine mispairs and may have evolved from MutT, an 8-oxo-dGTPase.Biochemistry, vol. 38, no. 20, May 1999, pp. 6374–79. Pubmed, doi:10.1021/bi990335x.
Journal cover image

Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

May 18, 1999

Volume

38

Issue

20

Start / End Page

6374 / 6379

Location

United States

Related Subject Headings

  • Sequence Homology, Amino Acid
  • Sequence Analysis
  • Protein Structure, Tertiary
  • Peptide Fragments
  • N-Glycosyl Hydrolases
  • Molecular Sequence Data
  • Kinetics
  • Humans
  • Guanine
  • Escherichia coli