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Crystal structures and biochemical analyses suggest a unique mechanism and role for human glycyl-tRNA synthetase in Ap4A homeostasis

Academic Article
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Overview

related to degree

  • Chong, Yeeting, Ph.D. in Biology, Scripps Research 2005 - 2011

authors

  • Guo, R. T.
  • Chong, Yeeting
  • Guo, Min
  • Yang, Xiang-Lei

publication date

  • October 2009

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Aminoacyl-tRNA synthetases catalyze the attachment of amino acids to their cognate tRNAs for protein synthesis. However, the aminoacylation reaction can be diverted to produce diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways. The only known mechanism for Ap4A production by a tRNA synthetase is through the aminoacylation reaction intermediate aminoacyl-AMP, thus making Ap4A synthesis amino acid-dependent. Here, we demonstrate a new mechanism for Ap4A synthesis. Crystal structures and biochemical analyses show that human glycyl-tRNA synthetase (GlyRS) produces Ap4A by direct condensation of two ATPs, independent of glycine concentration. Interestingly, whereas the first ATP-binding pocket is conserved for all class II tRNA synthetases, the second ATP pocket is formed by an insertion domain that is unique to GlyRS, suggesting that GlyRS is the only tRNA synthetase catalyzing direct Ap4A synthesis. A special role for GlyRS in Ap4A homeostasis is proposed.

subject areas

  • Adenosine Triphosphate
  • Binding Sites
  • Catalysis
  • Chromatography, Thin Layer
  • Crystallography, X-Ray
  • Dinucleoside Phosphates
  • Glycine
  • Glycine-tRNA Ligase
  • Homeostasis
  • Humans
  • Models, Biological
  • Models, Molecular
  • Molecular Conformation
  • Protein Binding
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Identity

PubMed Central ID

  • PMC2781443

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M109.030692

PubMed ID

  • 19710017
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Additional Document Info

start page

  • 28968

end page

  • 28976

volume

  • 284

issue

  • 42

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