Mutational switching of a yeast tRNA synthetase into a mammalian-like synthetase cytokine.
Aminoacyl-tRNA synthetases catalyze the attachment of amino acids to their cognate tRNAs. A link was recently established between protein biosynthesis and cytokine signal transduction. Human tyrosyl-tRNA synthetase can be split into two fragments, each of which has a distinct cytokine function. This activity is specific to the human enzyme. It is absent in the enzymes from lower organisms such as bacteria and yeast. Here, yeast tyrosyl-tRNA synthetase (TyrRS), which lacks cytokine activity, was used as a model to explore how a human tyrosyl-tRNA synthetase during evolution acquired novel functions beyond aminoacylation. We found that a rationally designed mutant yeast TyrRS(ELR) gained cytokine function. The mutant yeast enzyme gained this function without sacrifice of aminoacylation activity. Therefore, relatively simple alteration of a basic structural motif imparts cytokine activity to a tRNA synthetase while preserving its canonical function. Further work established that mutational switching of a yeast protein to a mammalian-like cytokine was specific to this synthetase and not to just any yeast ortholog of a mammalian cytokine.
Liu
Jianming
J
The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC-379, La Jolla, California 92037, USA.
Yang
Xiang-Lei
XL
Ewalt
Karla L
KL
Schimmel
Paul
P
D000215:Acylation; D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D016207:Cytokines / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D009504:Neutrophils / Q000201:enzymology / Q000502:physiology; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D014448:Tyrosine-tRNA Ligase / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
C102145:ARC1 protein, S cerevisiae; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; C077219:small inducible cytokine subfamily E, member 1; D014448:Tyrosine-tRNA Ligase