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

Publication ,  Journal Article
Riccio, AA; Bouvette, J; Perera, L; Longley, MJ; Krahn, JM; Williams, JG; Dutcher, R; Borgnia, MJ; Copeland, WC
Published in: Proc Natl Acad Sci U S A
August 9, 2022

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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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

August 9, 2022

Volume

119

Issue

32

Start / End Page

e2207459119

Location

United States

Related Subject Headings

  • Protein Multimerization
  • Mutant Proteins
  • Molecular Dynamics Simulation
  • Mitochondrial Proteins
  • Mitochondrial Diseases
  • Mass Spectrometry
  • Humans
  • DNA, Mitochondrial
  • DNA Replication
  • DNA Helicases
 

Citation

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Riccio, A. A., Bouvette, J., Perera, L., Longley, M. J., Krahn, J. M., Williams, J. G., … Copeland, W. C. (2022). Structural insight and characterization of human Twinkle helicase in mitochondrial disease. Proc Natl Acad Sci U S A, 119(32), e2207459119. https://doi.org/10.1073/pnas.2207459119
Riccio, Amanda A., Jonathan Bouvette, Lalith Perera, Matthew J. Longley, Juno M. Krahn, Jason G. Williams, Robert Dutcher, Mario J. Borgnia, and William C. Copeland. “Structural insight and characterization of human Twinkle helicase in mitochondrial disease.Proc Natl Acad Sci U S A 119, no. 32 (August 9, 2022): e2207459119. https://doi.org/10.1073/pnas.2207459119.
Riccio AA, Bouvette J, Perera L, Longley MJ, Krahn JM, Williams JG, et al. Structural insight and characterization of human Twinkle helicase in mitochondrial disease. Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2207459119.
Riccio, Amanda A., et al. “Structural insight and characterization of human Twinkle helicase in mitochondrial disease.Proc Natl Acad Sci U S A, vol. 119, no. 32, Aug. 2022, p. e2207459119. Pubmed, doi:10.1073/pnas.2207459119.
Riccio AA, Bouvette J, Perera L, Longley MJ, Krahn JM, Williams JG, Dutcher R, Borgnia MJ, Copeland WC. Structural insight and characterization of human Twinkle helicase in mitochondrial disease. Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2207459119.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

August 9, 2022

Volume

119

Issue

32

Start / End Page

e2207459119

Location

United States

Related Subject Headings

  • Protein Multimerization
  • Mutant Proteins
  • Molecular Dynamics Simulation
  • Mitochondrial Proteins
  • Mitochondrial Diseases
  • Mass Spectrometry
  • Humans
  • DNA, Mitochondrial
  • DNA Replication
  • DNA Helicases