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A short peptide insertion crucial for angiostatic activity of human tryptophanyl-tRNA synthetase

Nature Structural & Molecular Biology volume 11, pages 149156 (2004) | Download Citation

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Abstract

Human tryptophanyl-tRNA synthetase (TrpRS) is secreted into the extracellular region of vascular endothelial cells. The splice variant form (mini TrpRS) functions in vascular endothelial cell apoptosis as an angiostatic cytokine. In contrast, the closely related human tyrosyl-tRNA synthetase (TyrRS) functions as an angiogenic cytokine in its truncated form (mini TyrRS). Here, we determined the crystal structure of human mini TrpRS at a resolution of 2.3 Å and compared the structure with those of prokaryotic TrpRS and human mini TyrRS. Deletion of the tRNA anticodon-binding (TAB) domain insertion, consisting of eight residues in the human TrpRS, abolished the enzyme's apoptotic activity for endothelial cells, whereas its translational catalysis and cell-binding activities remained unchanged. Thus, we have identified the inserted peptide motif that activates the angiostatic signaling.

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Acknowledgements

We thank M. Ibba (Ohio State University) for helpful discussions during the manuscript preparation. We also thank M. Kawamoto and H. Sakai (Japanese Synchrotron Radiation Research Institute (JASRI)) for their help in data collection at SPring-8. This work was supported by a PRESTO Program grant from Japan Science and Technology and a Naito Foundation grant to O.N., and by a grant for National Creative Research Initiatives from the Ministry of Science and Technology, Korea to S.K.

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Affiliations

  1. Department of Biophysics and Biochemistry, Graduate School of Science, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

    • Yoshiaki Kise
    • , Toru Sengoku
    • , Ryohei Ishii
    •  & Shigeyuki Yokoyama
  2. National Creative Research Initiatives Center for ARS Network, College of Pharmacy, Seoul National University, Seoul 145-742, Korea.

    • Sang Won Lee
    • , Sang Gyu Park
    •  & Sunghoon Kim
  3. Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa 226-8501, Japan.

    • Shuya Fukai
    •  & Osamu Nureki
  4. RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.

    • Shigeyuki Yokoyama
    •  & Osamu Nureki
  5. PRESTO, Japan Science and Technology.

    • Osamu Nureki

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The authors declare no competing financial interests.

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Correspondence to Sunghoon Kim or Osamu Nureki.

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https://doi.org/10.1038/nsmb722

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