期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2207459119
关键词
mitochondrial DNA; Twinkle helicase; mitochondrial DNA replication; cryo-electron microscopy; progressive external ophthalmoplegia
资金
- Division of Intramural Research of the NIH, National Institute of Environmental Health Sciences (NIEHS) [Z01 ES065078, Z01 ES065080, Z01 ES043010, ZIC ES 103326]
- NIH [P41-GM103311]
In this study, the three-dimensional structures of human Twinkle W315L were determined for the first time using cryo-EM, providing insights into its function in mitochondrial DNA replication and associated diseases. The dynamic movement and molecular consequences of the W315L clinical variant were investigated, shedding light on the mechanism of mitochondrial diseases.
Twinkle is the mammalian helicase vital for replication and integrity of mitochondrial DNA. Over 90 Twinkle helicase disease variants have been linked to progressive external ophthalmoplegia and ataxia neuropathies among other mitochondrial diseases. Despite the biological and clinical importance, Twinkle represents the only remaining component of the human minimal mitochondrial replisome that has yet to be structurally characterized. Here, we present 3-dimensional structures of human Twinkle W315L. Employing cryo-electron microscopy (cryo-EM), we characterize the oligomeric assemblies of human full-length Twinkle W315L, define its multimeric interface, and map clinical variants associated with Twinkle in inherited mitochondrial disease. Cryo-EM, crosslinking-mass spectrometry, and molecular dynamics simulations provide insight into the dynamic movement and molecular consequences of the W315L clinical variant. Collectively, this ensemble of structures outlines a framework for studying Twinkle function in mitochondrial DNA replication and associated disease states.
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