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Sidan uppdaterades: 2012-09-11 15:12
| 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 |
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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