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Electrospray mass spectrometry study of protein folding using hydrogen/deuterium exchange

presented by

Larry Gross
Howard Hughes Medical Institute

September 23, 1997

The Scripps Research Institute, W.M. Keck Foundation Amphitheater


Background:

Dr. Gross received his B.S. in Chemistry from Ohio State University in 1977 and his Ph.D. in Analytical Chemistry from the University of California, Riverside in 1987. He then held post-doctoral appointments at the Ames Laboratory at Iowa State and later at the Upjohn Company in Michigan from 1991-1993. Since 1994 Larry has been working as a research specialist at the Howard Hughes Medical Institute labs in San Diego where his research includes the analysis of proteins and peptides, synthetic products, and fluorescent probes using electrospray mass spectrometry.

Abstract:

The past year has seen a great increase in the number of studies using hydrogen/ deuterium exchange and mass spectrometry to detect amide nitrogens protected by protein folding, by ligand binding, and to probe mechanisms of hydrogen exchange. The complementary nature of NMR and MS for these experiments was demonstrated by B. Chait in 1993, and was further developed for protein folding by C. Dobson (Science 1993, V262, P896). Professor Jennings and her group at UCSD are studying the cytokine IL-1beta because its size (17kDa) and beta-strand structure make it amenable to NMR. The experiments to be described by Dr. Larry Gross were designed such that the exchange was from deuterium to hydrogen, thus reversing the usual direction. As a result an increase in mass was measured versus the time allowed for folding, which recorded the folding pathway from the unfolded to the native state. The results of data collection and analysis indicate that the kinetic intermediate in the folding of IL1 is obligatory, which means that each molecule of protein must pass through a common configuration in the process of folding. This conclusion may potentially lead to a better understanding of this process, in terms of either a pathway or a folding funnel model.

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