Using Glycodendrimers to Elucidate the Importance of Multivalency in the Structures and Functions of Galectins

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With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Mary Cloninger from Montana State University to develop sugar-modified highly branched compounds to study the important roles that galectins play in cell-to-cell interactions. Galectins are carbohydrate binding proteins involved in many physiological functions that involve how cells interact and communicate with other cells and are linked to diseases such as fibrosis, cancer and heart disease. A set of highly branched molecules, called glycodendrimers, with varied numbers of sugars displayed on their surfaces will be synthesized. These glycodendrimers will be used in biochemical, structural, and cell biological studies to investigate the effects that carbohydrate binding has on how galectins interact with each other and how these protein interactions affect cell-to-cell interactions. Under this project, the PI will reach out to students from diverse populations to bring these students into the Cloninger research group through outreach programs with Flathead Valley Community College (FVCC) and local high schools. In addition, Dr. Cloninger and her undergraduate and graduate students will present their research to chemistry classes at four local high schools and give interested high school students opportunities to perform microscopy experiments at Montana State University.Although galectins play a critical role in cellular recognition processes through their binding interactions with cell surface carbohydrates, modulation of the interplay between their multivalent and monovalent functionalities is not well understood. Moreover, whether galectins from the three subfamilies have synergistic or distinct functions is currently unknown. The proposed research will use glycodendrimers to better understand galectin structure-function relationships. Lactose-functionalized glycodendrimers are ideal macromolecules with which to study multivalent carbohydrate-lectin interactions because both their size and the number of carbohydrate end groups can be systematically varied. Thus, glycodendrimers will be used to identify the role of the N-terminal domain in directing multivalent galectin-3/carbohydrate interactions. In addition, glycodendrimers will be used to evaluate whether galectins from the three subfamilies are working in concert to achieve increased specificity and selectivity in their multivalent interactions. Dynamic light scattering, transmission electron microscopy and fluorescence microscopy will be employed to visualize glycodendrimer-lectin interactions. In addition, cellular uptake, and cellular aggregation assays using a series of glycodendrimers binding to galectin-3 and to mixtures of galectins will be performed. Elucidating the key principles that guide multivalent interactions in complex environments is essential for understanding the role of multivalent associations between cell surface carbohydrates and galectins. In this regard, carbohydrate-functionalized dendrimers provide an ideal platform for the requisite systematic study of the role of multivalent interactions in carbohydrate-lectin binding.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.