The major focus of my research is the investigation of relationships between protein dynamics and function, including function in the context of the cell and/or organism. We use NMR spectroscopy as our primary research tool to measure internal motions of individual bonds within a protein. NMR is a powerful tool for extracting amplitudes and time scales of motion with atomic resolution, and is able to detect motions over a wide range of time scales (picoseconds to nanoseconds, microseconds to milliseconds, and seconds to hours). From our studies thus far, we have learned that a ligand binding event is communicated from the protein/ligand interface to remote regions of the protein, and that the entire protein structure can contribute significantly to the binding energetics. Our studies have focused on proteins involved in disease processes (e.g. the proto-oncoprotein Src, the Lyme's disease protein OspA, the amyloid precursor protein cytoplasmic tail APP-C), and have provided information to the scientific community that will assist in the development of novel therapeutic strategies. Our current objectives are focused on expanding our dynamics studies into thermodynamics and kinetics studies in order to obtain a more complete picture of the energy landscape of proteins. We are currently studying proline isomerization switches involved in Alzheimer`s disease and asthma, and in a fundamental coupling between innate immunity signaling and regulation of the actin cytoskeleton.
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.
My main teaching assignment is BioMG 6310, "Protein Structure and Function". In this course we explore topics ranging from evolution to the underlying principles of the two spectroscopic techniques available for determination of the three- dimensional structure of proteins, NMR spectroscopy and X-ray crystallography. Students acquire the knowledge needed to understand current literature on relationships between protein structure, function and dynamics.
I also teach a graduate level course, "Protein NMR Spectroscopy" (BioMG 7300). This course covers the theoretical framework (at the quantum mechanical level) for nuclear spin manipulations, and presents the fundamental tools for understanding and designing NMR pulse sequences. NMR data processing and analysis in terms of protein structure determination and dynamics measurements are also covered.
I occasionally teach mini-courses. I last taught a minicourse in Spring 2013, BioMG 7340-03 "Molecular Switches in Signaling and Disease". In three 2-hour meetings, this minicourse presented some fundamental switching mechanisms that regulate protein and cellular function. Examples where detailed mechanisms are understood were highlighted. In addition, molecular switches in the context of biological interaction networks were modeled using the online tool, Virtual Cell. The format of the class meetings was approximately 50% lecture and 50% workshop (exercises using Virtual Cell). Workshop exercises required students to bring their own laptop with wireless networking, and could be done individually or in groups of 2-3 people.
Awards and Honors
- Estevan Fuertes Award for Outstanding OADI Faculty Partner (2014) OADI
Presentations and Activities
- Investigations of a Molecular Switch to Derail Alzheimer's Disease. Technology Showcase. May 2014. Cornell CCTEC. Biotech Building, Cornell University.