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Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy

Fecha de publicación:

Autores de CIPF

Participantes ajenos a CIPF

  • Abbott, JA
  • Meyer-Schuman, R
  • Feely, S
  • Mademan, I
  • Oprescu, SN
  • Griffin, LB
  • Alberti, MA
  • Casasnovas, C
  • Aharoni, S
  • Basel-Vanagaite, L
  • Zuchner, S
  • De Jonghe, P
  • Baets, J
  • Shy, ME
  • Demeler, B
  • Antonellis, A
  • Francklyn, C

Grupos de Investigación

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.

Datos de la publicación

ISSN/ISSNe:
1059-7794, 1098-1004

HUMAN MUTATION  WILEY-BLACKWELL

Tipo:
Article
Páginas:
415-432
PubMed:
29235198

Citas Recibidas en Web of Science: 27

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Keywords

  • aminoacyl-tRNA synthetase; Charcot-Marie-Tooth disease type 2W; hereditary motor and sensory neuropathy; histidyl-tRNA synthetase

Campos de Estudio

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