title: Mutational separation of aminoacylation and cytokine activities of human tyrosyl-tRNA synthetase.
abstract: Aminoacyl tRNA synthetases are known for catalysis of aminoacylation. Significantly, some mammalian synthetases developed cytokine functions possibly linked to disease-causing mutations in tRNA synthetases. Not understood is how epitopes for cytokine signaling were introduced into catalytic scaffolds without disturbing aminoacylation. Here we investigate human tyrosyl-tRNA synthetase, where a catalytic-domain surface helix, next to the active site, was recruited for interleukin-8-like cytokine signaling. Taking advantage of our high resolution structure, the reciprocal impact of rational mutations designed to disrupt aminoacylation or cytokine signaling was investigated with multiple assays. The collective analysis demonstrated a protective fine-structure separation of aminoacylation from cytokine activities within the conserved catalytic domain. As a consequence, disease-causing mutations affecting cell signaling can arise without disturbing aminoacylation. These results with TyrRS also predict the previously unknown binding conformation of interleukin-8-like CXC cytokines.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Mili
authors.initials: M
authors.lastname: Kapoor
authors.forename: Francella J
authors.initials: FJ
authors.lastname: Otero
authors.forename: Bonnie M
authors.initials: BM
authors.lastname: Slike
authors.forename: Karla L
authors.initials: KL
authors.lastname: Ewalt
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
mesh_terms: D019943:Amino Acid Substitution; D049148:Aminoacylation; D055162:Biocatalysis; D020134:Catalytic Domain; D003198:Computer Simulation; D016207:Cytokines / Q000737:chemistry*; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D014448:Tyrosine-tRNA Ligase / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016207:Cytokines; D050505:Mutant Proteins; D014448:Tyrosine-tRNA Ligase