With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Sarah Michel from the University of Maryland-Baltimore to study the mechanism of action and key structure/function relationships for three "non-classical" zinc finger (ZF) proteins, (1) the Cleavage and Polyadenylation and Stimulating Factor (CPSF30), which plays a central role in pre-mRNA processing in all eukaryotes, and (2) the Neural Zinc Finger Factor-1 (NZF-1) and related (3) Myelin Transcription Factor 1 (MyT1), which play critical roles in the development of the central nervous system (CNS). A biochemical and biophysical approach will be taken to characterize the Zn(II) binding domains of CPSF30 and identify the RNA sequences recognized by the protein and characterize the Zn(II) binding domains NZF-1 and MyT1 and identify their DNA target sequences. This work should facilitate a molecular level understanding of the these protein-nucleic acid interactions.
Zinc Finger (ZF) proteins contain modular domains that coordinate zinc ions using a combination of four cysteine and/or histidine ligands to fold into specific three-dimensional structures. ZFs have critically important roles in modulating transcription and translation in all eukaryotes and show a remarkable capacity for highly selective nucleic acid recognition. While much is known about the metal-mediated folding and nucleic acid recognition properties of classical ZF proteins, very little is known about the biochemical mechanisms of the non-classical ZF proteins to be studied in this proposal. These studies aim to provide information on why Nature selects classical versus non-classical ZFs for a particular transcriptional and translational regulatory role. There is the potential for broader scientific impact on modes by which metal co-factored regulatory proteins operate in general. The graduate, undergraduate and high school students involved in the project will receive interdisciplinary training at the chemistry/molecular biology interface. There is a significant outreach component, particularly directed toward encouraging women to enter the STEM disciplines. This includes interaction with girls from a local high school and women from a local women's college, as well as female graduate students on the project. A "zinc finger lab" for high school girls enrolled in AP Biology is being developed.
