@article{RNACatalysis:Structure:1577,
      recid = {1577},
      author = {Dasgupta, Saurja},
      title = {RNA Catalysis: Structure, Function, and Evolution},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2018-08},
      pages = {356},
      abstract = {Catalytic RNA or ribozymes present excellent systems to  study the foundational principles of biological catalysis.  In addition, they serve as models for investigating RNA  structure and its relation to function. We report the first  crystal structures of the Varkud satellite (VS) ribozyme,  the largest among endonucleolytic ribozymes. The structures  reveal a modular organization, in which independently  folding domains are assembled into the functional  conformation of the ribozyme by three-way junctions. The  catalytic domain of the ribozyme recognizes and binds the  substrate through tertiary interactions, and substrate  docking is accompanied by remodeling of substrate structure  that results in the formation of a catalytically-relevant  active site. The catalytic strategies employed by the VS  bear resemblance to that used by protein and DNAzyme  ribonucleases, highlighting the robustness of the chemistry  of catalytic RNA cleavage. In addition, the active site of  the VS ribozyme is strikingly similar to that of the  hairpin and hammerhead ribozymes, although the three  endonucleolytic ribozymes have distinct sequences and  structures. The presence of these architectural features in  the context of what appears to be distinct mechanisms of  catalysis underscores their functional importance and  bolsters the case for convergent evolution. 

However, our  understanding of the possible mechanisms for the emergence  of distinct endonucleolytic ribozyme function during  evolution and the ease of access to distinct catalytic  motifs involved in RNA cleavage is limited. We have  explored the mutational connections between the VS, hairpin  and hammerhead ribozymes and delineated plausible pathways  by which these distinct ribonuclease motifs can be accessed  via intersection of their neutral networks. Intersections  between neutral networks are possible due to the existence  of bifunctional sequences that exhibit catalytic functions  corresponding to both networks. We have identified two such  bifunctional sequences that can support hairpin and VS, and  hammerhead and hairpin dual functions. Bifunctional  sequences present plausible evolutionary nodes toward  increasing complexity in functional RNA as illustrated by  the hammerhead, hairpin and VS ribozymes in our study. Our  results provide a framework to investigate the evolutionary  origins of distinct catalytic function in RNA.},
      url = {http://knowledge.uchicago.edu/record/1577},
      doi = {https://doi.org/10.6082/uchicago.1577},
}