Structural and Functional Studies of Mtr4 and the TRAMP RNA Surveillance Complex

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Project Summary Nuclear RNA processing and surveillance is a complex process involving multiple proteins and protein assemblies that identify and eventually degrade targeted RNA substrates. The RNA helicase, Mtr4, plays a central role in this process by providing a bridge between substrate targeting and RNA decay by the RNA exosome. RNA recognition is performed directly by Mtr4 and by various adaptor proteins that recruit Mtr4 to targeted substrates. A major challenge is to understand the molecular details of how these proteins interact with RNA substrates and with each other to achieve substrate specificity. Additionally, accessory domains within Mtr4 play important but poorly defined roles in substrate recognition and processing. Notably, the available structural data demonstrate that Mtr4 is a highly dynamic protein, but it is not known how protein dynamics relate to helicase function. This project seeks to define the molecular basis for Mtr4 function by employing a variety of biochemical, biophysical and structural approaches, supported by in vivo genetic analyses. The specific aims of this project are to (1) describe the role of Mtr4 accessory domains and (2) characterize interactions within the TRAMP (Trf4-Air2-Mtr4) complex. Undergraduate and graduate researchers with interests in future careers in biomedical research or medicine will be involved in the project.