Linda K. Nicholson


Research Focus

The overall objective of my research program is to gain a fundamental understanding of protein function and regulation from a perspective that includes both atomic resolution structure and dynamic fluctuations within this structure. I have exploited systems in which the regulation and/or function of a specific protein is amenable to study using biophysical methods, principally NMR spectroscopy. In recent years my work has focused on proteins that are regulated by phosphorylation (the cytoplasmic tail of the amyloid precursor protein and Ezrin), as well as proteins that facilitate key aspects of infection by pathogenic bacteria (OspA and AvrPto). The common element in these research endeavors is the establishment of relationships between atomic level structural and dynamic features of a specific protein and its function in the cell, with emphasis on proteins with an established role in disease. It is my opinion that one of the most exciting and important challenges in science today is to understand the relationships between protein dynamics and cellular dynamics. For cases in which a specific protein is identified as a key regulatory element of a given biological process, and for which a cellular output of the process can be measured, it should be possible to extract relationships between protein kinetics (and the actual intra- and intermolecular dynamics that facilitate activity) and the kinetics of the measured cellular output. Currently, my lab is investigating two such biological systems that are allowing us to begin to establish direct links between dynamics at the sub-molecular and cellular levels. In one system we are investigating the influence of the enzyme Pin1 on the proteolytic processing fate of the amyloid precursor protein, while in the second system we are examining molecular switches in innate immunity signaling, including links between the stimulation of Toll-like receptors and the dynamic remodeling of the actin cytoskeleton.

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