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

Abstract：

: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.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Korhonen JA,Pande V,Holmlund T,Farge G,Pham XH,Nilsson L,Falkenberg M

doi

10.1016/j.jmb.2008.01.035

subject

Has Abstract

pub_date

2008-03-28 00:00:00

pages

691-705

issue

3

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(08)00067-3

journal_volume

377

pub_type

杂志文章

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