Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA

Mitochondrial tRNAs are indispensable and yet underwent an extreme mutational erosion. The authors report the structures of a mitochondrial aaRS-tRNA complex and show how the most degenerated of all human mtRNAs is recognized by its cognate synthetase to maintain mitochondrial gene expression. Human mitochondrial gene expression relies on the specific recognition and aminoacylation of mitochondrial tRNAs (mtRNAs) by nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs). Despite their essential role in cellular energy homeostasis, strong mutation pressure and genetic drift have led to an unparalleled sequence erosion of animal mtRNAs. The structural and functional consequences of this erosion are not understood. Here, we present cryo-EM structures of the human mitochondrial seryl-tRNA synthetase (mSerRS) in complex with mtRNA(Ser(GCU)). These structures reveal a unique mechanism of substrate recognition and aminoacylation. The mtRNA(Ser(GCU)) is highly degenerated, having lost the entire D-arm, tertiary core, and stable L-shaped fold that define canonical tRNAs. Instead, mtRNA(Ser(GCU)) evolved unique structural innovations, including a radically altered T-arm topology that serves as critical identity determinant in an unusual shape-selective readout mechanism by mSerRS. Our results provide a molecular framework to understand the principles of mito-nuclear co-evolution and specialized mechanisms of tRNA recognition in mammalian mitochondrial gene expression.

Automated summary

This study reports the structures of a mitochondrial aaRS-tRNA complex and reveals the unique mechanism of substrate recognition and aminoacylation in severely degenerated mtRNA(Ser(GCU)). The findings provide a molecular framework to understand the principles of mito-nuclear co-evolution and specialized mechanisms of tRNA recognition in mammalian mitochondrial gene expression.