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

Artikel i vetenskaplig tidskrift
Författare Teresa Holmlund
Géraldine Farge
Vineet Pande
Jenny Korhonen
L Nilsson
Maria Falkenberg
Publicerad i Biochimica et biophysica acta
Volym 1792
Nummer/häfte 2
Sidor 132-9
ISSN 0006-3002
Publiceringsår 2009
Publicerad vid Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
Sidor 132-9
Språk en
Länkar dx.doi.org/10.1016/j.bbadis.2008.11...
Ämnesord 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
Ämneskategorier Kemi

Sammanfattning

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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