The scientists identified the specific molecular changes that enabled TrpRS to perform one function or another.
In the study, the scientists show that, for its role in protein synthesis, TrpRS is typically in its full-length form. This form of the molecule contains a tryptophan-binding pocket that enables it to bind with the amino acid and shepherd it to where it is needed in protein synthesis.
In the second active form, however, the protein must first be broken into fragments by the body, creating a piece called T2-TrpRS. With the removal of the end of the full-length protein (the N-domain), new grooves in the T2-TrpRS protein fragment are revealed. Containing the now-exposed tryptophan-binding pocket, the grooves fit together with side chains of another molecule, VE-cadherinknown to be indispensable for proper vascular development.
Interestingly, the new study found that tryptophan acts to inhibit of the vasculature function of TrpRS, locking the protein into its protein-synthesis form.
Yang notes that the therapeutic potential of TrpRS and other tRNA synthetases are particularly good because they normally exist in abundant amounts in the body.
"Naturally, you'd imagine the body's tolerance for such a protein is pretty good," she said, "and we could use the activated form of the molecule."
In addition, Yang points out that TrpRS is intriguing because it does not effect existing blood vessel growth, only new blood vessel formation, reducing the odds of negative side effects from its use.
|Contact: Keith McKeown|
Scripps Research Institute