Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia.

TitleStructure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia.
Publication TypeJournal Article
Year of Publication2004
AuthorsGraziewicz, MA, Longley, MJ, Bienstock, RJ, Zeviani, M, Copeland, WC
JournalNat Struct Mol Biol
Volume11
Issue8
Pagination770-6
Date Published2004 Aug
ISSN1545-9993
KeywordsAmino Acid Motifs, Bacterial Proteins, Catalytic Domain, Crystallography, X-Ray, DNA, DNA Polymerase gamma, DNA-Directed DNA Polymerase, Genes, Dominant, Glycine, Humans, Kinetics, Mitochondria, Models, Molecular, Mutagenesis, Site-Directed, Mutation, Nucleotides, Ophthalmoplegia, Chronic Progressive External, Protein Binding, Protein Folding, RNA-Directed DNA Polymerase, Structure-Activity Relationship, Tyrosine
Abstract

Progressive external ophthalmoplegia (PEO) is a mitochondrial disorder associated with mutations in the POLG gene encoding the mitochondrial DNA polymerase (pol gamma). Four autosomal dominant mutations that cause PEO encode the amino acid substitutions G923D, R943H, Y955C and A957S in the polymerase domain of pol gamma. A homology model of the pol gamma catalytic domain in complex with DNA was developed to investigate the effects of these mutations. Two mutations causing the most severe disease phenotype, Y955C and R943H, change residues that directly interact with the incoming dNTP. Polymerase mutants exhibit 0.03-30% wild-type polymerase activity and a 2- to 35-fold decrease in nucleotide selectivity in vitro. The reduced selectivity and catalytic efficiency of the autosomal dominant PEO mutants predict in vivo dysfunction, and the extent of biochemical defects correlates with the clinical severity of the disease.

DOI10.1038/nsmb805
Alternate JournalNat. Struct. Mol. Biol.
Citation Key10.1038/nsmb805
PubMed ID15258572