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Structure-function defects of the TWINKLE linker region in progressive external ophthalmoplegia.

Journal article
Authors Jenny A Korhonen
Vineet Pande
Teresa Holmlund
Géraldine Farge
Xuan Hoi Pham
Lennart Nilsson
Maria Falkenberg
Published in Journal of molecular biology
Volume 377
Issue 3
Pages 691-705
ISSN 1089-8638
Publication year 2008
Published at
Pages 691-705
Language en
Keywords Cloning, Molecular, DNA Helicases, chemistry, genetics, DNA Primase, chemistry, DNA Replication, DNA, Mitochondrial, genetics, metabolism, Humans, Models, Molecular, Mutation, Ophthalmoplegia, Chronic Progressive External, genetics, Protein Conformation, Structure-Activity Relationship
Subject categories Chemistry


TWINKLE is the helicase at the mitochondrial DNA (mtDNA) replication fork in mammalian cells. Mutations in the PEO1 gene, which encodes TWINKLE, cause autosomal dominant progressive external ophthalmoplegia (AdPEO), a disorder associated with deletions in mtDNA. Here, we characterized seven different AdPEO-causing mutations in the linker region of TWINKLE and we identified distinct molecular phenotypes. For some mutations, protein hexamerization and DNA helicase activity are completely abolished whereas others display more subtle effects. To better understand these distinct phenotypes, we constructed a molecular model of TWINKLE based on the three-dimensional structure of the bacteriophage T7 gene 4 protein. The structural model explains the molecular phenotypes and also predicts the functional consequences of other AdPEO-causing mutations. Our findings provide a molecular platform for further studies in cell- and animal-based model systems and demonstrate that knowledge of the bacteriophage T7 DNA replication machinery may be key to understanding the molecular and phenotypic consequences of mutations in the mtDNA replication apparatus.

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