Crystal structure of human wildtype and S581L-mutant glycyl-tRNA synthetase, an enzyme underlying distal spinal muscular atrophy.
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.
Cader
Muhammed Z
MZ
Henry Wellcome Building for Gene Function, MRC Functional Genetics Unit, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom.
Ren
Jingshan
J
James
Paul A
PA
Bird
Louise E
LE
Talbot
Kevin
K
Stammers
David K
DK
D019943:Amino Acid Substitution; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D049310:Distal Myopathies / Q000201:enzymology* / Q000235:genetics; D006032:Glycine-tRNA Ligase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007930:Leucine / Q000737:chemistry; D008958:Models, Molecular; D009134:Muscular Atrophy, Spinal / Q000201:enzymology* / Q000235:genetics; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D020125:Mutation, Missense; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D046249:Transfer RNA Aminoacylation / Q000235:genetics
D050505:Mutant Proteins; D016601:RNA-Binding Proteins; D012694:Serine; D006032:Glycine-tRNA Ligase; D007930:Leucine