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Cocrystal Structures of Glycyl-tRNA Synthetase in Complex with tRNA Suggest Multiple Conformational States in Glycylation*

X. Qin,Z. Hao,Q. Tian,Zhemin Zhang,Chun Zhou,W. Xie

Published 2014 in Journal of Biological Chemistry

ABSTRACT

Background: The molecular basis for catalysis by human glycyl-tRNA synthetase (hGlyRS) is unclear. Results: hGlyRS-tRNA complex structures are reported, and the molecular details for enzymatic recognition are elucidated. Conclusion: hGlyRS catalysis involves multiple conformational changes, and insertions 1 and 3 may facilitate tRNA binding. Significance: Understanding the catalytic pathway also provides insights into the role of hGlyRS in disease. Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl-tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. In the past decade, mutations of human GlyRS (hGlyRS) were also found to be associated with Charcot-Marie-Tooth disease. However, the mechanisms of traditional and alternative functions of hGlyRS are poorly understood due to a lack of studies at the molecular basis. In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. The cocrystal structures suggest that insertions 1 and 3 work together with the active site in a cooperative manner to facilitate efficient substrate binding. Both the enzyme and tRNA molecules undergo significant conformational changes during glycylation. A working model of multiple conformations for hGlyRS catalysis is proposed based on the crystallographic and biochemical studies. This study provides insights into the catalytic pathway of hGlyRS and may also contribute to our understanding of Charcot-Marie-Tooth disease.

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