CAREER: Chemical Genetic Dissection of Cell Signaling

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With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Chao Zhang from the University of Southern California to develop a chemical approach to investigate the mechanism by which information is transduced in cells. To adjust and adapt their behavior to external environments, cells rely on intricate communication and control networks comprised of thousands of proteins. While some of the proteins which participate in these communication networks are very similar to each other in sequence and structure, they frequently have non-overlapping functions. How proteins similar in sequence and structure carry out distinct functions in the cell is poorly understood, partly due to a lack of tools that can effectively distinguish between these proteins. Dr. Zhang will work on a novel approach to address this problem. The method is based on the introduction of a reactive feature into a protein of interest, which would enable the selective binding to the protein of small molecules that recognize this feature. The new method will be applied in the study of the roles of closely-related proteins in cell signal transduction. The graduate and undergraduate students who will work on this project will receive an interdisciplinary training in diverse fields including synthetic chemistry, biochemistry and cell biology. The research project will also be related to an outreach program aimed at the education of students from high schools and colleges on the mechanism and development of AIDS drugs.The objective of this research is to develop a chemical-genetic approach for the study of the cellular functions of closely-related, cell-signaling proteins. The central premise is that a reactive cysteine residue introduced in the target protein can serve as an affinity- and specificity element, making possible the identification of potent and specific small molecules that bind to the proteins. Building upon preliminary results obtained at the University of Southern California, the researchers will test this premise. First specific electrophilic inhibitors for a cysteine-mutant of BRAF kinase will be identified first in vitro and then studied in vivo. The isoform-specific inhibitors will be used to determine the roles of two RAF isoforms in the cell cycle. The research is expected to provide new knowledge about a fundamental cell-signaling pathway and to reveal novel functions of vital signaling proteins.