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Protein Conformation and Dynamics Research
Jennifer Lee, Principal Investigator
Research Overview
Our research interests are focused on elucidating the role of protein conformations and dynamics in biomedical problems. Current studies are aimed at neuronal and membrane-associated proteins: (1) aggregation of amyloidogenic proteins and mechanisms of their function and dysfunction (2) transmembrane proteins involved in the intracellular transport and regulation of glutamate. The overarching objective is not only to characterize specific proteins, protein-membrane, and protein-drug interactions, but also to measure dynamics underlying individual biochemical pathways. This research program employs a variety of laser spectroscopic techniques including fluorescence energy transfer and electron transfer kinetics as well as tools from biochemistry and molecular biology for functional studies.
A schematic representation of Förster energy transfer (FRET) in protein conformation measurements. When an acceptor molecule is in close proximity (10– 100 Å) to a donor fluorophore, non-radiative energy transfer results in quenching of donor fluorescence (faster decay). As FRET efficiency is dependent on the inverse sixth power of the donor/accepter separation, distances between donor and acceptor molecules attached site-specifically to a protein can be extracted.
Amyloidogenic Proteins
Many neurodegenerative diseases, such as Parkinson’s disease, are associated with the deposition and accumulation of specific peptide/protein aggregates in the brain. The role of these proteinacious materials (amyloid) in the pathogenic process is unclear. A crucial question is whether a misfolded protein is directly implicated in the pathogenic mechanism. Surprising recent discoveries also point to a functional role for amyloid fibrils in several organisms including humans! Understanding the mechanisms of these proteins therefore promises insight into the pathophysiology of these disorders and guidance for the development of therapeutics in addition to its fundamental value.
Ion Receptors and Transporters
Glutamate is the major excitatory neurotransmitter in the central nervous system. Release, detection, and reuptake of this small molecule is essential to neuronal communication. Two types of transmembrane proteins are involved in the detection and reuptake of glutamate; ionotropic glutamate receptor ion channels and glutamate transporters. Understanding the mechanisms of these proteins is at the forefront of membrane protein biophysics; though some protein structures recently have been determined, little is known about the dynamic movements that are principal to this machinery. Our studies seek to map the protein conformational landscapes during ion binding and transport.
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