Three-dimensional structure model and predicted ATP interaction rewiring of a deviant RNA ligase 2. (December 2015)

• Record Type: Journal Article
• Authors: Moreira, Sandrine; Noutahi, Emmanuel; Lamoureux, Guillaume; Burger, Gertraud
• Is Part Of: BMC structural biology. Volume 15:Number 1(2015)
• Page Start: 1
• Page End: 15
• Publication Date: 2015-12
• Subjects: Protein structure -- Molecular dynamics simulation -- Protein evolution; Molecular biology -- Periodicals; Macromolecular Systems -- Periodicals; Models, Structural -- Periodicals; 572.33
• DOI: 10.1186/s12900-015-0046-0
• Languages: English
• ISSNs: 1472-6807

Abstract

Abstract Background RNA ligases 2 are scarce and scattered across the tree of life. Two members of this family are well studied: the mitochondrial RNA editing ligase from the parasitic trypanosomes (Kinetoplastea), a promising drug target, and bacteriophage T4 RNA ligase 2, a workhorse in molecular biology. Here we report the identification of a divergent RNA ligase 2 (DpRNL) fromDiplonema papillatum (Diplonemea), a member of the kinetoplastids' sister group. Methods We identified DpRNL with methods based on sensitive hidden Markov Model. Then, using homology modeling and molecular dynamics simulations, we established a three dimensional structure model of DpRNL complexed with ATP and Mg2+. Results The 3D model ofDiplonema was compared with available crystal structures fromTrypanosoma brucei, bacteriophage T4, and two archaeans. Interaction of DpRNL with ATP is predicted to involve double π-stacking, which has not been reported before in RNA ligases. This particular contact would shift the orientation of ATP and have considerable consequences on the interaction network of amino acids in the catalytic pocket. We postulate that certain canonical amino acids assume different functional roles in DpRNL compared to structurally homologous residues in other RNA ligases 2, a reassignment indicative of constructive neutral evolution. Finally, both structure comparison and phylogenetic analysis show that DpRNL is not specifically related to RNA ligases from trypanosomes, suggesting a unique adaptation of the latter for RNA editing, after the split of diplonemids and kinetoplastids. Conclusion Homology modeling and molecular dynamics simulations strongly suggest that DpRNL is an RNA ligase 2. The predicted innovative reshaping of DpRNL's catalytic pocket is worthwhile to be tested experimentally.