Pro-Angiogenic Activity Exposed in Crystal Structure of Enzyme Fragment

If there is one thing more important than knowing that a fragment of an enzyme is active in promoting a certain cellular signaling event, it is knowing why that fragment is active.

The enzyme in question is a fragment of a human tyrosyl-tRNA synthetase (TyrRS), one of 20 ancient enzymes that attach the correct amino acid to a tRNA as the first step in the synthesis of proteins. This "mini-TyrRS" fragment is active in certain cell-signaling pathways, such as angiogenesis. Strangely, mini-TyrRS' corresponding full-length enzyme is not active in those same pathways.

A recent paper reporting the 1.18 Angstrom resolution structure of mini-TyrRS, which was published in the Proceedings of the National Academy of Sciences, answers why this is so. In the structure, a critical motif of three amino acids, Glu-Leu-Arg, is exposed, and the structure suggests that in the full-length TyrRS, this triad is buried in the enzyme by an additional flap—the domain that's missing in mini-TyrRS. Cleave this flap, and the fragment becomes active as a promoter of angiogenesis.

The research was led by Research Fellow Xiang-Lei Yang and Professor Paul Schimmel, both of The Scripps Research Institute, and was carried out in collaboration with researchers at Syrrx, Inc., a local biotechnology company.

Schimmel, who is Ernest and Jean Hahn Professor of Molecular Biology and Chemistry at TSRI and a member of The Skaggs Institute for Chemical Biology, has been studying tRNA synthetases for a number of years. His group first discovered the pro-angiogenic properties of mini-TyrRS and the anti-angiogenic properties of the enzyme's tryptophanyl cousin mini-TrpRS a few years ago.

There is considerable therapeutic interest in pro-angiogenic factors like mini TyrRS—in applications where revascularization of the heart is needed, or where peripheral artery disease has reduced collateral blood flow, for instance. Likewise, there is therapeutic interest in the anti-angiogenic properties of mini-TrpRS, since abnormal angiogenesis is behind the vast majority of diseases that cause catastrophic vision loss.

Recently, Schimmel and several other TSRI investigators were awarded a five-year, $9.6-million grant from the National Eye Institute to study further the inhibitory properties of mini-TrpRS and to develop ways to use it in patients with neovascular eye disease.

To read the article, "Crystal structure of a human aminoacyl-tRNA synthetase cytokine" by Xiang-Lei Yang, Robert J. Skene, Duncan E. McRee, and Paul Schimmel, please see: http://



Structure of pro-angiogenic human tyrosyl-tRNA synthetase modeled with its cognate tRNA.