Project Summary Alanna Schepartz proposes to significantly alter the undergraduate course of chemistry study at Yale to provide early, hands-on exposure to one of the fastest-growing areas of modern chemistry—chemical biology. She will create a pair of year-long courses—Chemical Biology and Chemical Biology Laboratory—that begin in the second semester of the sophomore year. This pair of courses will serve several purposes. First, they will illustrate to undergraduates, early in their careers, that chemical biology is an exciting, dynamic, and expanding field. Second, these courses will add depth and breadth to the ability of students to comprehend and apply biochemistry and molecular and cellular biology. Third, and perhaps most uniquely, they will demonstrate that the pursuit of knowledge through creative and rigorous research—the work that scientists actually do—is intellectually satisfying and fun.
The lecture course will provide a sophisticated survey of the field, with case studies and articles from primary literature. The laboratory course will be open-ended and research-driven, with publications, presentations, and summer research. An essential component of both courses will be close contact between undergraduates and graduate student mentors, many of whom will be women. The chemical biology option represents an extraordinary opportunity to improve the statistics of women in chemistry by providing undergraduates with early, positive experiences in science and graduate students with early, positive mentoring experiences. Dr. Schepartz anticipates that 60 undergraduate students and 20 graduate students will participate each year.
Research Summary Dr. Schepartz's research reflects broad interests within the field of chemical biology. Current lines of inquiry include how cells effectively use a limited number of proteins to achieve a precisely controlled and robust gene-regulatory network; how this network is usurped when cells succumb to viral attack; and how, inspired by the viral hijackers, one can design miniature proteins that mimic (and sometimes surpass) the functional properties of proteins found in nature.
Much of her research has focused on understanding and controlling the specificity of interactions between and among proteins and DNA. In early work Dr. Schepartz's group discovered that the DNA specificity of a bZIP protein can be controlled with a structurally tunable metal complex that alters the orientation of the protein in the DNA major groove. They also discovered that DNA specificity can be controlled by an intrinsic bend that preorganizes DNA for binding by some proteins and not others. Most recently, Dr. Schepartz's group discovered that many bZIP and bHLHzip proteins bind DNA as monomers, dimerizing while DNA-bound, and that this monomer-binding pathway represents the most rapid search method for locating specific DNA.
Her group has also explored how protein-protein interactions influence DNA specificity in the context of viral proteins that hijack cellular transcription factors to aid viral replication. They reported that the HTLV-I Tax protein and the HBV pX protein increase the DNA affinity of cellular bZIP proteins by stabilizing bZIP-DNA interactions and not by stabilizing bZIP dimerization. Her group also reported that pX diminishes the inherent specificity of the monomer-binding pathway of bZIPs, providing a molecular explanation for aberrant transcriptional activation during HBV infection. Most recently, they reported that pX effectively bypasses the phosphorylation event that activates certain bZIP proteins, short-circuiting natural signal transduction pathways linking elevated cAMP levels and transcriptional activation. This work provides a direct link between HBV infection and the development of hepatocellular carcinoma.
Their most recent efforts focus on an exciting strategy for designing miniature proteins that mimic the functional properties of proteins found in nature. In their strategy, called "protein grafting," essential recognition groups are grafted onto a small, well-folded protein core, producing a miniature protein that is preorganized for binding another macromolecule.
Last updated October 2002
