Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2

Ekaterine Kartvelishvili, Dmitry Tworowski, Hilary Vernon, Nina Moor, Jing Wang, Lee Jun Wong, Zofia Chrzanowska-Lightowlers, Mark Safro

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Mutations in the mitochondrial aminoacyl-tRNA synthetases (mtaaRSs) can cause profound clinical presentations, and have manifested as diseases with very selective tissue specificity. To date most of the mtaaRS mutations could be phenotypically recognized, such that clinicians could identify the affected mtaaRS from the symptoms alone. Among the recently reported pathogenic variants are point mutations in FARS2 gene, encoding the human mitochondrial PheRS. Patient symptoms range from spastic paraplegia to fatal infantile Alpers encephalopathy. How clinical manifestations of these mutations relate to the changes in three-dimensional structures and kinetic characteristics remains unclear, although impaired aminoacylation has been proposed as possible etiology of diseases. Here, we report four crystal structures of HsmtPheRS mutants, and extensive MD simulations for wild-type and nine mutants to reveal the structural changes on dynamic trajectories of HsmtPheRS. Using steady-state kinetic measurements of phenylalanine activation and tRNAPhe aminoacylation, we gained insight into the structural and kinetic effects of mitochondrial disease-related mutations in FARS2 gene.

Original languageEnglish
Pages (from-to)1505-1516
Number of pages12
JournalProtein Science
Issue number8
StatePublished - 1 Aug 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 The Protein Society


  • X-ray structures
  • kinetic experiments
  • mitochondrial PheRS
  • mitochondrial diseases
  • molecular dynamic simulations
  • mutants


Dive into the research topics of 'Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2'. Together they form a unique fingerprint.

Cite this