Structural Studies Of Post-Transcriptional Gene Regulation

National Institute Of Environmental Health Sciences

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Abstract

RNA regulation provides a mechanism to rapidly control gene expression in response to stimuli, including environmental changes. This project seeks to generate and utilize structural information to enhance our understanding of these processes with an emphasis on the importance of RNA target specificity for proper gene regulation. In this fiscal year, we have studied the atomic structures and functions of different RNA-binding proteins that regulate germline development. We have also studied the atomic structure and RNA recognition properties of enzymes that participate in the maturation of transfer RNA (tRNA). Finally, we are developing designed RNA-binding proteins to disrupt translation. A major focus of our group is to understand the function of Pumilio/FBF (PUF) proteins. We determined the first crystal structure of a PUF protein in complex with RNA, which allowed us to understand the RNA recognition properties of PUF proteins and have extended these structural studies to a variety of PUF proteins. In this fiscal year we have continued our studies of how PUF proteins function in partnership with other RNA regulatory proteins and how designed PUF proteins can be utilized to modulate RNA function. We published a manuscript in Nucleic Acids Research describing a crystal structure of the RNA-recognition domain of the tRNA processing enzyme, protein-only RNase P, in complex with tRNA. With our collaborators, we examined the effects of mutations on enzymatic activity and tRNA recognition and identified a novel RNA recognition mode for pentatricopeptide repeats. This mechanism of recognition is distinct from the sequence-specific RNA recognition that had been previously demonstrated. In addition, we compared the RNA recognition mode that we discovered with those of other tRNA-binding molecules and identified recognition strategies that are conserved across different proteins and ribozymes. The manuscript was highlighted as a Breakthrough paper. Breakthrough papers are those that appear to solve a long-standing problem in their field or provide exceptional new insight and understanding into an area of research that will clearly motivate and guide new research opportunities and directions. They highlight the top 1 to 2% of papers that NAR receives for publication. They are selected based on nominations by authors and/or reviewers, and on the subsequent recommendation of the reviewers and editorial board members.