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

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dc.contributor.authorAbbott, Jamie A.
dc.contributor.authorMeyer-Schuman, Rebecca
dc.contributor.authorLupo, Vicenzo
dc.contributor.authorFeeley, Shawna
dc.contributor.authorMademan, Ines
dc.contributor.authorOprescu, Stephanie N.
dc.contributor.authorGriffin, Laurie B.
dc.contributor.authorAlberti, M. Antonia
dc.contributor.authorCasasnovas, Carlos
dc.contributor.authorAharoni, Sharon
dc.contributor.authorBasel-Vanagaite, Lina
dc.contributor.authorZuchner, Stephan
dc.contributor.authorDe Jonghe, Peter
dc.contributor.authorBaets, Jonathan
dc.contributor.authorShy, Michael E.
dc.contributor.authorEspinos, Carmen
dc.contributor.authorDemeler, Borries
dc.contributor.authorAntonellis, Anthony
dc.contributor.authorFrancklyn, Christopher
dc.date.accessioned2021-09-22T19:59:39Z
dc.date.available2021-09-22T19:59:39Z
dc.date.issued2018
dc.descriptionAccepted author manuscripten_US
dc.description.abstractHistidyl-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.en_US
dc.description.peer-reviewYesen_US
dc.identifier.citationAbbott, J. A., Meyer-Schuman, R., Lupo, V., Feely, S., Mademan, I., Oprescsu, S. N., Griffin, L. B., Alberti, M. A., Casasnovas, C., Aharoni, S., Basel-Vanagaite, L, Zuchner, S., De Jonghe, P., Baets, J., Shy, M. E., Espinos, C., Demeler, B., Antonellis, A., & Francklyn, C. (2018). Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy. Human Mutation, 39(3), 415-432. https://doi.org/10.1002/humu.23380en_US
dc.identifier.urihttps://hdl.handle.net/10133/6032
dc.language.isoen_USen_US
dc.publisherWileyen_US
dc.publisher.departmentDepartment of Chemistry and Biochemistryen_US
dc.publisher.facultyArts and Scienceen_US
dc.publisher.institutionUniversity of Vermonten_US
dc.publisher.institutionUniversity of Michigan Medical Schoolen_US
dc.publisher.institutionCentro de Investigacion Principe Felipe (CIPF)en_US
dc.publisher.institutionUniversity of Iowa Hospitals and Clinicsen_US
dc.publisher.institutionCenter for Molecular Neurologyen_US
dc.publisher.institutionInstitute Born-Bungeen_US
dc.publisher.institutionHospital Universitario de Bellvitgeen_US
dc.publisher.institutionTel Aviv Universityen_US
dc.publisher.institutionSchneider Children's Medical Center of Israelen_US
dc.publisher.institutionRabin Medical Centeren_US
dc.publisher.institutionUniversity of Miami Miller School of Medicineen_US
dc.publisher.institutionAntwerp University Hospitalen_US
dc.publisher.institutionUniversity of Texas Health Science Center at San Antonioen_US
dc.publisher.institutionUniversity of Lethbridgeen_US
dc.publisher.urlhttps://doi.org/10.1002/humu.23380en_US
dc.subjectHereditary motor and sensory neuropathyen_US
dc.subjectHistidyl-tRNA synthetaseen_US
dc.subject.lcshAminoacyl-tRNA synthetases
dc.subject.lcshNeuropathy
dc.subject.lcshNerves, Peripheral--Diseases
dc.titleSubstrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathyen_US
dc.typeArticleen_US
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