Journal article
Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy
Human mutation, Vol.39(3), pp.415-432
03/2018
DOI: 10.1002/humu.23380
PMCID: PMC5983030
PMID: 29235198
Abstract
Histidyl-tRNA synthetase (HARS) ligates histidine to cognate tRNA molecules, which is required for protein translation. Mutations in HARS cause the dominant axonal peripheral neuropathy Charcot-Marie-Tooth disease type 2W (CMT2W); however, the precise molecular mechanism remains undefined. Here, we investigated three HARS missense mutations associated with CMT2W (p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly). The three mutations localize to the HARS catalytic domain and failed to complement deletion of the yeast ortholog (HTS1). Enzyme kinetics, differential scanning fluorimetry (DSF), and analytical ultracentrifugation (AUC) were employed to assess the effect of these substitutions on primary aminoacylation function and overall dimeric structure. Notably, the p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly HARS substitutions all led to reduced aminoacylation, providing a direct connection between CMT2W-linked HARS mutations and loss of canonical ARS function. While DSF assays revealed that only one of the variants (p.Val155Gly) was less thermally stable relative to wild-type, all three HARS mutants formed stable dimers, as measured by AUC. Our work represents the first biochemical analysis of CMT-associated HARS mutations and underscores how loss of the primary aminoacylation function can contribute to disease pathology.
Details
- Title: Subtitle
- Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy
- Creators
- Jamie A Abbott - Department of Biochemistry, College of Medicine, University of Vermont, Burlington, VermontRebecca Meyer-Schuman - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MichiganVincenzo Lupo - Unit of Genetics and Genomics of Neuromuscular Disorders, Centro de Investigación Príncipe Felipe (CIPF), Valencia, SpainShawna Feely - Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IowaInès Mademan - Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerpen, BelgiumStephanie N Oprescu - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MichiganLaurie B Griffin - Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MichiganM Antonia Alberti - Department of Neurology, Hospital Universitario de Bellvitge, Barcelona, SpainCarlos Casasnovas - Department of Neurology, Hospital Universitario de Bellvitge, Barcelona, SpainSharon Aharoni - Institute of Child Neurology, Schneider Children's Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Tel Aviv, IsraelLina Basel-Vanagaite - Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, IsraelStephan Züchner - Dr John T McDonald Foundation Department of Human Genetics & John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FloridaPeter De Jonghe - Department of Neurology, Antwerp University Hospital, Antwerpen, BelgiumJonathan Baets - Department of Neurology, Antwerp University Hospital, Antwerpen, BelgiumMichael E Shy - Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IowaCarmen Espinós - Unit of Genetics and Genomics of Neuromuscular Disorders, Centro de Investigación Príncipe Felipe (CIPF), Valencia, SpainBorries Demeler - Department of Biochemistry, The University of Texas Health Sciences at San Antonio, San Antonio, TexasAnthony Antonellis - Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MichiganChristopher Francklyn - Department of Biochemistry, College of Medicine, University of Vermont, Burlington, Vermont
- Resource Type
- Journal article
- Publication Details
- Human mutation, Vol.39(3), pp.415-432
- DOI
- 10.1002/humu.23380
- PMID
- 29235198
- PMCID
- PMC5983030
- NLM abbreviation
- Hum Mutat
- ISSN
- 1059-7794
- eISSN
- 1098-1004
- Publisher
- United States
- Grant note
- P30 CA054174 / NCI NIH HHS\nT32 GM007863 / NIGMS NIH HHS\nF30 NS092238 / NINDS NIH HHS\nT32 GM007315 / NIGMS NIH HHS\nT32 HL007594 / NHLBI NIH HHS\nT32 GM007544 / NIGMS NIH HHS\nR01 GM054899 / NIGMS NIH HHS\nU54 NS065712 / NINDS NIH HHS\nR01 GM118647 / NIGMS NIH HHS
- Language
- English
- Date published
- 03/2018
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984070254602771
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