Crystal structure of human wildtype and S581L-mutant glycyl-tRNA synthetase, an enzyme underlying distal spinal muscular atrophy.

Journal article

Dominant mutations in the ubiquitous enzyme glycyl-tRNA synthetase (GlyRS), including S581L, lead to motor nerve degeneration. We have determined crystal structures of wildtype and S581L-mutant human GlyRS. The S581L mutation is approximately 50A from the active site, and yet gives reduced aminoacylation activity. The overall structures of wildtype and S581L-GlyRS, including the active site, are very similar. However, residues 567-575 of the anticodon-binding domain shift position and in turn could indirectly affect glycine binding via the tRNA or alternatively inhibit conformational changes. Reduced enzyme activity may underlie neuronal degeneration, although a dominant-negative effect is more likely in this autosomal dominant disorder.

Authors: Cader, M; Ren, J; James, P; Bird, L; Talbot, K

• Publication status: Published
• Journal: FEBS letters
• Volume: 581
• Issue: 16
• Pages: 2959-2964
• Publication date: 2007-06-01
• DOI: 10.1016/j.febslet.2007.05.046
• EISSN: 1873-3468
• ISSN: 0014-5793
• Language: English
• Keywords: Dimerization; Crystallography, X-Ray; Distal Myopathies; Muscular Atrophy, Spinal; Models, Molecular; Mutation, Missense; Humans; Transfer RNA Aminoacylation; Leucine; Glycine-tRNA Ligase; Binding Sites; Serine; Mutant Proteins; Amino Acid Substitution; RNA-Binding Proteins