Highly differentiated motifs responsible for two cytokine activities of a split human tRNA synthetase.
While native human tyrosyl-tRNA synthetase (TyrRS) is inactive as a cell-signaling molecule, it can be split into two distinct cytokines. The enzyme is secreted under apoptotic conditions in culture where it is cleaved into an N-terminal fragment that harbors the catalytic site and into a C-domain fragment found only in the mammalian enzymes. The N-terminal fragment is an interleukin-8 (IL-8)-like cytokine, whereas the released C-domain is an endothelial-monocyte-activating polypeptide II (EMAP II)-like cytokine. Although the IL-8-like activity of the N-fragment depends on an ELR motif found in alpha-chemokines and conserved among mammalian TyrRSs, here we show that a similar (NYR) motif in the context of a lower eukaryote TyrRS does not confer the IL8-like activity. We also show that a heptapeptide from the C-domain has EMAP II-like chemotaxis activity for mononuclear phagocytes and polymorphonuclear leukocytes. Eukaryote proteins other than human TyrRS that have EMAP II-like domains have variants of the heptapeptide motif. Peptides based on these sequences are inactive as cytokines. Thus, the cytokine activities of split human TyrRS depend on highly differentiated motifs that are idiosyncratic to the mammalian system.
Wakasugi
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The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Schimmel
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D000595:Amino Acid Sequence; D000818:Animals; D002634:Chemotaxis, Leukocyte; D016207:Cytokines; D019281:Dimerization; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism; D010586:Phagocytes / Q000737:chemistry / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014448:Tyrosine-tRNA Ligase / Q000378:metabolism*
D016207:Cytokines; D016209:Interleukin-8; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; D014448:Tyrosine-tRNA Ligase