This proposal focuses on a recently described structural motif, called the """"""""leucine zipper"""""""", that is found in some DNA binding proteins. The long-term objectives of the proposed research are to understand the relationship between structure and function in leucine zippers, and to understand how this new class of proteins bind DNA in a sequence specific manner. The proposed research is significant for understanding protein-DNA interactions, specific protein-protein interactions, transcriptional activation, and oncogenesis.
The specific aims of the research are: (1) to determine the structure of a synthetic peptide corresponding to the leucine zipper region of a yeast transcriptional activator called GCN4, using crystallography (in collaboration with a crystallographer) and 2D-NMR methods; (2) to determine how a 60-residue fragment of GCN4, that includes the leucine zipper, is capable of binding DNA in a sequence-specific manner, using 2D-NMR and mutagenesis studies: and (3) to determine the mechanism for specific heterodimer formation by two leucine zipper peptides that correspond to regions of the nuclear oncogene products Fos and Jun, using structural studies and synthesis of variant peptides.
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