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Structure-function defects of the twinkle amino-terminal region in progressive external ophthalmoplegia.

Journal article
Authors Teresa Holmlund
Géraldine Farge
Vineet Pande
Jenny Korhonen
L Nilsson
Maria Falkenberg
Published in Biochimica et biophysica acta
Volume 1792
Issue 2
Pages 132-9
ISSN 0006-3002
Publication year 2009
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 132-9
Language en
Keywords Amino Acid Sequence, DNA Helicases, chemistry, genetics, isolation & purification, metabolism, DNA Replication, genetics, DNA, Mitochondrial, genetics, Models, Molecular, Molecular Sequence Data, Mutation, genetics, Ophthalmoplegia, Chronic Progressive External, enzymology, genetics, Protein Structure, Quaternary, Recombinant Proteins, genetics, metabolism
Subject categories Chemistry


TWINKLE is a DNA helicase needed for mitochondrial DNA replication. In lower eukaryotes the protein also harbors a primase activity, which is lost from TWINKLE encoded by mammalian cells. Mutations in TWINKLE underlie autosomal dominant progressive external ophthalmoplegia (adPEO), a disorder associated with multiple deletions in the mtDNA. Four different adPEO-causing mutations (W315L, K319T, R334Q, and P335L) are located in the N-terminal domain of TWINKLE. The mutations cause a dramatic decrease in ATPase activity, which is partially overcome in the presence of single-stranded DNA. The mutated proteins have defects in DNA helicase activity and cannot support normal levels of DNA replication. To explain the phenotypes, we use a molecular model of TWINKLE based on sequence similarities with the phage T7 gene 4 protein. The four adPEO-causing mutations are located in a region required to bind single-stranded DNA. These mutations may therefore impair an essential element of the catalytic cycle in hexameric helicases, i.e. the interplay between single-stranded DNA binding and ATP hydrolysis.

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