Schimmel Lab - The Scripps Research Institute

Aminoacyl-tRNA synthetases: Biology & Disease

Aminoacyl-tRNA synthetases establish the rules of the genetic code by joining amino acids to tRNAs that bear the anticodon triplets corresponding to the attached amino acids. The enzymes are thought to be among the earliest proteins to appear, in the transition from a putative RNA world to the theater of proteins. Over their long evolutionary history, aminoacyl-tRNA synthetases have been conscripted by nature to perform a broad repertoire of additional functions beyond their primary role in translation.

Two particular interesting examples of novel aminoacyl-tRNA synthetase function are the recent discoveries from the Schimmel laboratory that fragments of closely related human tyrosyl- and tryptophanyl-tRNA synthetases are active in angiogenesis signaling pathways. The tyrosyl-tRNA synthetase fragment, mini-TyrRS, has proangiogenic activity while two tryptophanyl-tRNA synthetase fragments, mini-TrpRS and T2-TrpRS are antiangiogenic. These activities have been demonstrated in a variety of in vitro cell-based assays and also in vivo using chick embryos, and in the neonatal and adult mouse. The full-length, native enzymes are inactive in these same assays. Activation of angiogenesis activity requires fragment production from the native enzymes by protease cleavage or by translation of alternatively spliced pre-mRNA. Thus these tRNA synthetases link translation to major cell-signaling pathways in mammalian cells. Importantly, recent results with animals suggest that these tRNA synthetases might be developed into therapeutic applications for the treatment of macular degeneration, an ophthalmic disease, and ultimately in the treatment of certain cancers.

Research on the exact molecular mechanisms by which the biological fragments of human tyrosyl- and tryptophanyl-tRNA synthetases exert their respective angiogenic and antiangiogenic effects is ongoing in the Schimmel laboratory. We have recently identified VE-cadherin as the cellular receptor for T2-TrpRS. The interaction of T2-TrpRS with VE-cadherin correlates strongly with inhibition of angiogenesis-related signaling pathways. VE-cadherin provides a link, therefore, between T2-TrpRS and blocking of new blood vessel formation.

Figure Legend

VE-cadherin reconstitutes binding of T2-TrpRS to Cos cells.
Cos7 cells transiently transfected with VE-cadherin cDNA plus GFP or GFP alone show specific binding of Alexa546-T2-TrpRS only to VE-cadherin expressing cells.