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Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE helicase.

Journal article
Authors Bradley Peter
Geraldine Farge
Carlos Pardo-Hernandez
Stefan Tångefjord
Maria Falkenberg
Published in Human molecular genetics
Volume 28
Issue 7
Pages 1090–1099
ISSN 1460-2083
Publication year 2019
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 1090–1099
Language en
Links dx.doi.org/10.1093/hmg/ddy415
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Structural Biology, Molecular biology

Abstract

TWINKLE is the helicase involved in replication and maintenance of mitochondrial DNA (mtDNA) in mammalian cells. Structurally, TWINKLE is closely related to the bacteriophage T7 gp4 protein and comprises a helicase and primase domain joined by a flexible linker region. Mutations in and around this linker region are responsible for autosomal dominant progressive external ophthalmoplegia (adPEO), a neuromuscular disorder associated with deletions in mtDNA. The underlying molecular basis of adPEO-causing mutations remains unclear, but defects in TWINKLE oligomerisation are thought to play a major role. In this study, we have characterised these disease variants by single-particle electron microscopy and can link the diminished activities of the TWINKLE variants to altered oligomeric properties. Our results suggest that the mutations can be divided into those that (i) destroy the flexibility of the linker region, (ii) inhibit ring-closure, and (iii) change the number of subunits within a helicase ring. Furthermore, we demonstrate that wild-type TWINKLE undergoes large-scale conformational changes upon NTP binding and that this ability is lost in the disease-causing variants. This represents a substantial advancement in the understanding of the molecular basis of adPEO and related pathologies and may aid in the development of future therapeutic strategies.

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