Structural Divergence of the Group I Intron-Binding Surface in Fungal Mitochondrial Tyrosyl-tRNA Synthetases that Function in RNA Splicing [RNA]

April 1st, 2016 by Lamech, L. T., Saoji, M., Paukstelis, P. J., Lambowitz, A. M.

The mitochondrial tyrosyl-tRNA synthetases (mtTyrRSs) of Pezizomycotina fungi, a subphylum that includes many pathogenic species, are bifunctional proteins that both charge mt tRNATyr and promote the splicing of autocatalytic group I introns. Previous studies showed that one of these proteins, Neurospora crassa CYT-18, binds group I introns by using both its N-terminal catalytic and C-terminal anticodon-binding domains and that the catalytic domain uses a newly evolved group I intron-binding surface, which includes an N-terminal extension and two small insertions (insertions 1 and 2) with distinctive features not found in non-splicing mtTyrRSs. To explore how this RNA-binding surface diverged to accommodate different group I introns in other Pezizomycotina fungi, we determined X-ray crystal structures of C-terminally truncated Aspergillus nidulans and Coccidioides posadasii mtTyrRSs. Comparisons with previous N. crassa CYT-18 structures and a structural model of the A. fumigatus mtTyrRS showed that the overall topology of the group I intron-binding surface is conserved, but with variations in key intron-binding regions, particularly the Pezizomycotina-specific insertions. These insertions, which arose by expansion of flexible termini or internal loops, show greater variation in structure and amino acids potentially involved in group I intron binding than do neighboring protein core regions that also function in intron binding but may be more constrained to preserve mtTyrRS activity. Our results suggest a structural basis for the intron-specificity of different Pezizomycotina mtTyrRSs, highlight flexible terminal and loop regions as major sites for enzyme diversification, and identify targets for therapeutic intervention by disrupting an essential RNA-protein interaction in pathogenic fungi.
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