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Models of protein folding and aggregation

John Finke

Appointment Period: 1998-2000, Grant Years: [13,14,15]

John FinkeModels of Protein Folding and Aggregation. The study of intracellular protein aggregation in vivo requires (1) a reliable model of folding in vitro and (2) detailed structural information of the protein being studied. My first research goal focused on integrating the existing structural data with protein folding studies to develop a model for the folding of the protein interleukin-1beta (IL-1 beta). My second goal was to use the folding model to develop the mechanism of IL-1 beta aggregation in an insoluble inactive state known as "inclusion bodies". My third goal was to use this model to identify kinetic states within the folding/aggregation pathways and target them with binding by "aggregation inhibitor" compounds.

PUBLICATIONS (resulting from this training, and some recent ones)

Finke JM, Roy M, Zimm BH, Jennings PA. (2000) Aggregation events occur prior to stable intermediate formation during refolding of interleukin 1beta. Biochemistry. 39:575-83.

Finke JM, Gross LA, Ho HM, Sept D, Zimm BH, Jennings PA. (2000) Commitment to folded and aggregated states occurs late in interleukin-1 beta folding. Biochemistry. 39:15633-42.

Finke JM, Jennings PA. (2002) Interleukin-1 beta folding between pH 5 and 7: experimental evidence for three-state folding behavior and robust transition state positions late in folding. Biochemistry 41:15056-67.

Finke JM, Cheung MS, Onuchic JN. (2004) A structural model of polyglutamine determined from a host-guest method combining experiments and landscape theory. Biophys J. 87(3):1900-18.

Roy M, Chavez LL, Finke JM, Heidary DK, Onuchic JN, Jennings PA. (2005) The native energy landscape for interleukin-1beta. Modulation of the population ensemble through native-state topology. J Mol Biol. 348:335-47.

Finke JM, Onuchic JN. (2005) Equilibrium and kinetic folding pathways of a TIM barrel with a funneled energy landscape. Biophys J. 89:488-505. Finke JM, Jennings PA, Lee JC, Onuchic JN, Winkler JR. (2007) Equilibrium unfolding of the poly-(glutamic acid)20 helix. Biopolymers. [Mar 16, Epub ahead of print]