Structural insight and characterization of human Twinkle helicase in mitochondrial disease.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Riccio, AA; Bouvette, J; Perera, L; Longley, MJ; Krahn, JM; Williams, JG; Dutcher, R; Borgnia, MJ; Copeland, WC

Published Date

  • August 9, 2022

Published In

Volume / Issue

  • 119 / 32

Start / End Page

  • e2207459119 -

PubMed ID

  • 35914129

Pubmed Central ID

  • PMC9371709

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.2207459119

Language

  • eng

Conference Location

  • United States