ZFIN ID: ZDB-PUB-160629-1
Unique domain appended to vertebrate tRNA synthetase is essential for vascular development
Xu, X., Yi Shi, Y., Zhang, H.-M., Swindell, E.C., Marshall, A.G., Guo, M., Kishi, S., Yang, X.-L.
Date: 2012
Source: Nature communications   3: 681 (Journal)
Registered Authors: Kishi, Shuji, Swindell, Eric C.
Keywords: Biological sciences, Biochemistry, Developmental biology, Molecular biology
MeSH Terms:
  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Aminoacylation
  • Animals
  • Blood Vessels/abnormalities
  • Blood Vessels/cytology*
  • Cell Nucleus/metabolism*
  • Crystallography, X-Ray
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Neovascularization, Physiologic
  • Nuclear Localization Signals
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Serine-tRNA Ligase/chemistry*
  • Serine-tRNA Ligase/genetics
  • Serine-tRNA Ligase/metabolism*
  • Signal Transduction
  • Vascular Endothelial Growth Factor A/metabolism
  • Zebrafish
  • Zebrafish Proteins/chemistry*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 22353712 Full text @ Nat. Commun.
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.