title: Three-dimensional structure model and predicted ATP interaction rewiring of a deviant RNA ligase 2.
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) from Diplonema 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 of Diplonema was compared with available crystal structures from Trypanosoma 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry and Robert-Cedergren Centre for Bioinformatics and Genomics, Université de Montréal, Montreal, QC, Canada. sandrine.moreira@umontreal.ca.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Moreira
authors.affiliation: Department of Biochemistry, currently Département d'informatique et de recherche opérationnelle (DIRO), Université de Montréal, Montreal, QC, Canada. fmr.noutahi@umontreal.ca.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Noutahi
authors.affiliation: Department of Chemistry and Biochemistry, Centre for Research in Molecular Modeling (CERMM), Groupe d'étude des protéines membranaires (GÉPROM), Regroupement québécois de recherche sur la fonction, l'ingénierie et les applications des protéines (PROTEO), Concordia University, Montreal, QC, Canada. Guillaume.Lamoureux@concordia.ca.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lamoureux
authors.affiliation: Department of Biochemistry and Robert-Cedergren Centre for Bioinformatics and Genomics, Université de Montréal, Montreal, QC, Canada. gertraud.burger@umontreal.ca.
authors.forename: Gertraud
authors.initials: G
authors.lastname: Burger
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D020134:Catalytic Domain; D056898:Euglenozoa / Q000737:chemistry / Q000201:enzymology / Q000235:genetics*; D008274:Magnesium / Q000378:metabolism; D008390:Markov Chains; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010802:Phylogeny; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011130:RNA Ligase (ATP) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D040681:Structural Homology, Protein
chemical_list: D015800:Protozoan Proteins; D000255:Adenosine Triphosphate; D011130:RNA Ligase (ATP); D008274:Magnesium