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Structural insight and characterization of human Twinkle helicase in mitochondrial disease

Amanda A Riccio1, Jonathan Bouvette2, Lalith Perera3

  • 1Mitochondrial DNA Replication group, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709.

Proceedings of the National Academy of Sciences of the United States of America
|August 1, 2022
PubMed

Insights

Researchers have determined the 3D structures of human Twinkle helicase, crucial for mitochondrial DNA replication. This breakthrough provides a framework for understanding Twinkle-related inherited mitochondrial diseases.

Area of Science:

  • Molecular biology
  • Genetics
  • Biochemistry

Background:

  • Twinkle is an essential mammalian helicase for mitochondrial DNA (mtDNA) replication and stability.
  • Over 90 disease variants of Twinkle helicase are associated with mitochondrial disorders, including progressive external ophthalmoplegia and ataxia neuropathies.
  • Twinkle is the last uncharacterized component of the human minimal mitochondrial replisome.

Purpose of the Study:

  • To present the 3D structures of human Twinkle helicase, specifically the W315L variant.
  • To characterize the oligomeric assemblies and multimeric interface of full-length human Twinkle.
  • To map clinical variants of Twinkle linked to inherited mitochondrial diseases.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to determine the 3D structures.
  • Crosslinking-mass spectrometry and molecular dynamics simulations were employed.
  • Analysis of oligomeric assemblies, multimeric interfaces, and variant consequences.

Main Results:

  • The study presents the 3D structures of human Twinkle W315L.
  • Oligomeric assemblies and the multimeric interface of human Twinkle were characterized.
  • Insights into the dynamic movement and molecular effects of the W315L variant were obtained.

Conclusions:

  • The determined structures provide a framework for understanding Twinkle's role in mtDNA replication.
  • This work facilitates the study of Twinkle function in inherited mitochondrial diseases.
  • Structural insights can guide future research into Twinkle-associated pathologies.
Keywords:
Twinkle helicasecryo-electron microscopymitochondrial DNAmitochondrial DNA replicationprogressive external ophthalmoplegia

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