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

Cader, Muhammed Z.; Ren, Jingshan; James, Paul A.; Bird, Louise E.; Talbot, Kevin; Stammers, David K.

doi:10.1016/j.febslet.2007.05.046

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Volume 581, Issue 16 , Pages 2959-2964, 26 June 2007

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

Edited by Hans Eklund

Muhammed Z. Cader
- Henry Wellcome Building for Gene Function, MRC Functional Genetics Unit, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom
- Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
Jingshan Ren
- Division of Structural Biology and Oxford Protein Production Facility, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom
Paul A. James
- Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
Louise E. Bird
- Division of Structural Biology and Oxford Protein Production Facility, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom
Kevin Talbot
- Henry Wellcome Building for Gene Function, MRC Functional Genetics Unit, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom
- Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
David K. Stammers
- Division of Structural Biology and Oxford Protein Production Facility, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom
- Corresponding author. Fax: +44 1865 287547.

Received 14 March 2007; received in revised form 15 May 2007; accepted 16 May 2007. published online 30 May 2007.

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 ∼50Å 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.