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://
www.pnas.org/cgi/doi/10.1073/pnas.242611799.
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Structure of pro-angiogenic human tyrosyl-tRNA
synthetase modeled with its cognate tRNA.
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