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

Abstract

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: Muhammed Z Cader, Jingshan Ren, Paul A James, Louise E Bird, Kevin Talbot, David K Stammers
• Journal: FEBS letters (FEBS Lett) Vol. 581 Issue 16 Pg. 2959-64 (Jun 26 2007) ISSN: 0014-5793 [Print] England
• PMID: 17544401 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Mutant Proteins
• RNA-Binding Proteins
• Serine
• Glycine-tRNA Ligase
• Leucine

Topics

• Amino Acid Substitution
• Binding Sites
• Crystallography, X-Ray
• Dimerization
• Distal Myopathies (enzymology, genetics)
• Glycine-tRNA Ligase (chemistry, genetics, metabolism)
• Humans
• Leucine (chemistry)
• Models, Molecular
• Muscular Atrophy, Spinal (enzymology, genetics)
• Mutant Proteins (chemistry, metabolism)
• Mutation, Missense
• RNA-Binding Proteins (chemistry, metabolism)
• Serine (chemistry)
• Transfer RNA Aminoacylation (genetics)