Crystal structures and biochemical analyses suggest a unique mechanism and role for human glycyl-tRNA synthetase in Ap4A homeostasis.
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.
Guo
Rey-Ting
RT
Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Chong
Yeeting E
YE
Guo
Min
M
Yang
Xiang-Lei
XL
D000255:Adenosine Triphosphate / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis; D002855:Chromatography, Thin Layer / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015226:Dinucleoside Phosphates / Q000737:chemistry* / Q000502:physiology*; D005998:Glycine / Q000737:chemistry; D006032:Glycine-tRNA Ligase / Q000737:chemistry* / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding
D015226:Dinucleoside Phosphates; C020733:diadenosine tetraphosphate; D000255:Adenosine Triphosphate; D006032:Glycine-tRNA Ligase; D005998:Glycine