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

Lookup NU author(s): Professor Zofia Chrzanowska-Lightowlers

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2017 The Authors Protein Science published by Wiley Periodicals, Inc. on behalf of The Protein Society. 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.


Publication metadata

Author(s): Kartvelishvili E, Tworowski D, Vernon H, Moor N, Wang J, Wong L-J, Chrzanowska-Lightowlers Z, Safro M

Publication type: Article

Publication status: Published

Journal: Protein Science

Year: 2017

Volume: 26

Issue: 8

Pages: 1505-1516

Print publication date: 01/08/2017

Online publication date: 17/04/2017

Acceptance date: 11/04/2017

Date deposited: 14/06/2017

ISSN (print): 0961-8368

ISSN (electronic): 1469-896X

Publisher: Wiley-Blackwell

URL: https://doi.org/10.1002/pro.3176

DOI: 10.1002/pro.3176


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