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 journalArticle

Abstract

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 (US)
JournalProtein Science
DOIs
StateAccepted/In press - 2017

Fingerprint

Mutation
Kinetics
Supravalvular Aortic Stenosis
Aminoacylation
Genes
RNA, Transfer, Phe
Amino Acyl-tRNA Synthetases
Mitochondrial Diseases
Organ Specificity
Paraplegia
Phenylalanine
Point Mutation
Library Catalogs
Buccal Administration
Cape Verde
Cyclic AMP Receptor Protein
Cytochrome c Group
Spontaneous Fractures
Trajectories
Globin Zinc Insulin

Keywords

  • Kinetic experiments
  • Mitochondrial diseases
  • Mitochondrial PheRS
  • Molecular dynamic simulations
  • Mutants
  • X-ray structures

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Kartvelishvili, E., Tworowski, D., Vernon, H., Moor, N., Wang, J., Wong, L. J., ... Safro, M. (2017). Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2. Protein Science. DOI: 10.1002/pro.3176

Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2. / Kartvelishvili, Ekaterine; Tworowski, Dmitry; Vernon, Hilary; Moor, Nina; Wang, Jing; Wong, Lee Jun; Chrzanowska-Lightowlers, Zofia; Safro, Mark.

In: Protein Science, 2017.

Research output: Contribution to journalArticle

Kartvelishvili, E, Tworowski, D, Vernon, H, Moor, N, Wang, J, Wong, LJ, Chrzanowska-Lightowlers, Z & Safro, M 2017, 'Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2' Protein Science. DOI: 10.1002/pro.3176
Kartvelishvili E, Tworowski D, Vernon H, Moor N, Wang J, Wong LJ et al. Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2. Protein Science. 2017. Available from, DOI: 10.1002/pro.3176

Kartvelishvili, Ekaterine; Tworowski, Dmitry; Vernon, Hilary; Moor, Nina; Wang, Jing; Wong, Lee Jun; Chrzanowska-Lightowlers, Zofia; Safro, Mark / Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2.

In: Protein Science, 2017.

Research output: Contribution to journalArticle

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