.svg) National Institute of General Medical Sciences |
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National Biomedical Resource for |
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Alpha-synuclein is a neuronal protein that has been genetically linked to Parkinson's disease and is found deposited as amyloid fibril aggregates in the Lewy body deposits that are characteristic of this debilitating disorder. Our studies of alpha-synuclein have revealed that the protein possesses unusual structural properties both in its free state in aqueous solution and bound to lipid membranes. The specific aim of the research we are doing at ACERT is to use ESR to help us compare the structural properties of synuclein bound to large lipid vesicles with the properties that we have observed using solution state NMR from protein bound to lipid-mimetic detergent micelles. The capabilities that make ESR uniquely suitable for this project are its applicability to systems that are much larger than those that can be used in solution NMR studies, and its ability to measure long distances between spin labels, which far exceeds the range of the NOE effect typically used to measure distances in NMR studies. Our preliminary work on the project has resulted in the successful production of double spin-labeled samples of alpha-synuclein bound to detergent micelles, and the acquisition of double quantum spectra that are consistent with the expected distance between the two labels based on our NMR work. The results also suggested several possible modifications to our sample preparation protocols that should improve the quality of the data, and we are currently implementing these modifications. We will collect additional data in the next few months to verify the expected improvements. Subsequently, we will expand the number of double-labeled synuclein samples, and begin our comparative studies of their topology in the presence of detergent micelles versus phospholipid vesicles based on long-range intramolecular distances. Publication: P.P. Borbat, T.F. Ramlall, J.H. Freed, and D. Eliezer, J. Am. Chem. Soc., 128, 10004-05 (2006); no PMCID |
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D. Eliezer (Department of Biochemistry and Program in Structural Biology, Weill Medical College of Cornell University, New York) P. P. Borbat, J. H. Freed (ACERT) |
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ACERT is supported by grant 1R24GM146107 from the National Institute of General Medical Sciences (NIGMS), part of the National Institutes of Health. |
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