Tryptophanyl-tRNA synthetase (mini TrpRS)
Homo sapiens (human)
In protein synthesis transfer RNAs selectively bind amino acids and transport them to the messenger RNAs. There, the amino acids are released from the tRNAs and integrated into the newly forming peptide chain. Aminoacyl-tRNA synthetases (aaRSs) are enzymes which are responsible for the selective bonding between an amino acid and the corresponding tRNA. It has also been observed that some aaRSs are being released by the cells during apoptosis (cell suicidal death) to engage in vessel formation regulation. Tryptophanyl-tRNA synthetase (TrpRS) is one of them.
Human TrpRS belongs to class I aminoacyl-tRNA synthetases ( class II aaRSs have a different structure of the catalytic domain ). It is a homo-dimer with each subunit comprising of ~500 amino acid residues. The structure shown here is of the spliced monomer, called mini TrpRS, which lacks the first 46 residues. It is very interesting that mini TrpRS is an angiostatic, i.e. it suppresses new vessel formation, while the full-length TrpRS does not show such activity . The structure of human mini TrpRS can be divided in four distinct domains : N-terminal domain (residues 82-154); Rossmann fold nucleotide-binding domain ( residues 155-347); CP1 domain ( residues 247-292) , included in the Rossmann fold and located at the interface of the two monomers connecting them to form the dimer; and TAB (tRNA anticodon-binding) domain (residues 348-471). This structure is very similar to the structures of two other aaRSs, prokaryotic TrpRS and human mini TyrRS ( tyrosyl-tRNA synthetase) - if the Rossmann fold domains are superimposed, we get r.m.s.d. (root mean square deviation) of 1.66 A and 1.43 A respectively. Amazingly, those two enzymes have an exactly opposite function - they are angiogenic cytokines! So what makes mini TrpRS so special? Comparison with the structures of the above proteins shows that mini TrpRS has four unique domains: the afore-mentioned N-terminal domain (M1); a loop structure of residues 293-304 (M2), inserted in the CP1 domain ; residues 381-390 (M3) in the TAB domain; and the C-terminal helix (M4). Mutagenic experiments with four mutants of mini TrpRS, each of them made be removing one of the four unique domains , M1 to M4, showed that the nested M3 loop in the TAB domain is the one responsible for the angiostatic activity of mini TrpRS. It is astonishing to see how a small change of only 8 residues in the structure can reverse the function of an enzyme. The structure of miniTrp can become a useful template for the design of anticancer drugs, because formation of tumors is accompanied by anomalous angiogenesis.
Protein Data Bank (PDB)
author: Rossen Apostolov