Structure of Human Cytosolic Phenylalanyl-tRNA Synthetase: Evidence for Kingdom-Specific Design of the Active Sites and tRNA Binding Patterns

SummaryThe existence of three types of phenylalanyl-tRNA synthetase (PheRS), bacterial (αβ)2, eukaryotic/archaeal cytosolic (αβ)2, and mitochondrial α, is a prominent example of structural diversity within the aaRS family. PheRSs have considerably diverged in primary sequences, domain compositions, and subunit organizations. Loss of the anticodon-binding domain B8 in human cytosolic PheRS (hcPheRS) is indicative of variations in the tRNAPhe binding and recognition as compared to bacterial PheRSs. We report herein the crystal structure of hcPheRS in complex with phenylalanine at 3.3 Å resolution. A novel structural module has been revealed at the N terminus of the α subunit. It stretches out into the solvent of ∼80 Å and is made up of three structural domains (DBDs) possessing DNA-binding fold. The dramatic reduction of aminoacylation activity for truncated N terminus variants coupled with structural data and tRNA-docking model testify that DBDs play crucial role in hcPheRS activity.

► For the first time crystal structure of eukaryotic (αβ)2 PheRS has been determined
► Three DNA/dsRNA-binding domains are located at the N terminus of the α subunit
► N terminus of the α subunit plays a vital role in the tRNAPhe binding and recognition
► Architecture of synthetic and editing active sites of the PheRS is kingdom dependent.