title: Unique domain appended to vertebrate tRNA synthetase is essential for vascular development.
abstract: New domains were progressively added to cytoplasmic aminoacyl transfer RNA (tRNA) synthetases during evolution. One example is the UNE-S domain, appended to seryl-tRNA synthetase (SerRS) in species that developed closed circulatory systems. Here we show using solution and crystal structure analyses and in vitro and in vivo functional studies that UNE-S harbours a robust nuclear localization signal (NLS) directing SerRS to the nucleus where it attenuates vascular endothelial growth factor A expression. We also show that SerRS mutants previously linked to vasculature abnormalities either deleted the NLS or have the NLS sequestered in an alternative conformation. A structure-based second-site mutation, designed to release the sequestered NLS, restored normal vasculature. Thus, the essential function of SerRS in vascular development depends on UNE-S. These results are the first to show an essential role for a tRNA synthetase-associated appended domain at the organism level, and suggest that acquisition of UNE-S has a role in the establishment of the closed circulatory systems of vertebrates.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Zhang
authors.forename: Eric C
authors.initials: EC
authors.lastname: Swindell
authors.forename: Alan G
authors.initials: AG
authors.lastname: Marshall
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.forename: Shuji
authors.initials: S
authors.lastname: Kishi
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D049148:Aminoacylation; D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities / Q000166:cytology*; D002467:Cell Nucleus / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D018919:Neovascularization, Physiologic; D019913:Nuclear Localization Signals; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012714:Serine-tRNA Ligase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D019913:Nuclear Localization Signals; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; D012714:Serine-tRNA Ligase