title: Dissociating quaternary structure regulates cell-signaling functions of a secreted human tRNA synthetase.
abstract: Many tRNA synthetases are homodimers that are catalytically inactive as monomers. An example is the 528-amino acid human tyrosyl-tRNA synthetase, which is made up of an N-terminal catalytic unit (TyrRS(Mini)) and a 164-amino acid C-domain. Although native TyrRS has no known cytokine functions, natural proteolysis of secreted TyrRS releases TyrRS(Mini), which not only has the same aminoacylation activity as native TyrRS but also has strong activity for stimulating migration of polymorphonuclear leukocytes. The migration-stimulating activity is dependent on an ELR tripeptide motif, similar to that in CXC cytokines like IL-8, and also has the familiar bell-shaped concentration dependence seen for CXC cytokines. Here we show that in contrast to IL-8, where the bell-shaped dependence arises from the effects of CXCR1/2 receptor internalization, TyrRS(Mini) does not induce internalization of CXCR1/2. A rationally designed non-associating monomer and a non-dissociating dimer were constructed. With these constructs, the bell-shaped concentration dependence of leukocyte migration was shown to arise from the agonist (for migration) activity of the catalytically inactive monomer and the antagonist activity of the catalytically active dimer. Thus, the dissociating quaternary structure of TyrRS(Mini) regulates two opposing cytokine activities and suggests the possibility of dissociating quaternary structures regulating novel functions of other tRNA synthetases.
authors.affiliation: Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: My-Nuong
authors.initials: MN
authors.lastname: Vo
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
mesh_terms: D020816:Amino Acid Motifs; D002465:Cell Movement / Q000502:physiology*; D016207:Cytokines / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014448:Tyrosine-tRNA Ligase / Q000737:chemistry / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D016207:Cytokines; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D014448:Tyrosine-tRNA Ligase