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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1792

Article

Holmlund, Teresa³  Farge, Geraldine³  Pande, Vineet²  Korhonen, Jenny³  Nilsson, Lennart²  Falkenberg, Maria^1,3 

[1] Univ Gothenburg, Dept Med Biochem & Cell Biol, SE-40530 Gothenburg, Sweden

[2] Karolinska Inst, Dept Biosci & Nutr, SE-14157 Huddinge, Sweden

[3] Karolinska Inst, Div Metab Dis, Dept Lab Med, SE-14186 Stockholm, Sweden

关键词: DNA replication;    Mitochondrion;    DNA helicase;    TWINKLE;   

DOI  :  10.1016/j.bbadis.2008.11.009

来源: Elsevier

【 摘 要 】

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. (c) 2008 Elsevier B.V. All rights reserved. IF

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