Structural analysis of human ATE1 isoforms and their interactions with Arg-tRNA.

Posttranslational protein arginylation has been shown as a key regulator of cellular processes in eukaryotes by affecting protein stability, function, and interaction with macromolecules. Thus, the enzyme Arginyltransferase and its targets, are of immense interest to modulate cellular processes in the normal and diseased state. While the study on the effect of this posttranslational modification in mammalian systems gained momentum in the recent times, the detail structures of human ATE1 (ATE1) enzymes has not been investigated so far. Thus, the purpose of this study was to predict the overall structure and the structure function relationship of ATE1 enzyme and its four isoforms. The structure of four ATE1 isoforms were modelled and were docked with 3'end of the Arg-tRNA which acts as arginine donor in the arginylation reaction, followed by MD simulation. All the isoforms showed two distinct domains. A compact domain and a somewhat flexible domain as observed in the RMSF plot. A distinct similarity in the overall structure and interacting residues were observed between ATE1-1 and X4 compared to ATE1-2 and 5. While the putative active sites of all the ATE1 isoforms were located at the same pocket, differences were observed in the active site residues across ATE1 isoforms suggesting different substrate specificity. Mining of nsSNPs showed several nsSNPs including cancer associated SNPs with deleterious consequences on ATE1 structure and function. Thus, the current study for the first time shows the structural differences in the mammalian ATE1 isoforms and their possible implications in the function of these proteins.Communicated by Ramaswamy H. Sarma.