Podium Presentation in Room 5 on Wednesday at 9:40 (Chair: Stephen Pennington)
Authors: John R. Yates, III, Casimir Bamberger, Hyunsoo Yu, and Sandra Pankow
INTRODUCTION: Proteins have exquisite three-dimensional structure. Their structures dictate the functions and interactions within the cell. Most of what we know about the structures of proteins comes from methods like x-ray crystallography, NMR and more recently cyro-EM. These methods are all in vitro methods that often look at proteins as single entities or as a protein complex. What is often missing is the in vivo context to the protein structure, e.g. what is the structure that exists in the cell. Several mass spectrometry-based methods are emerging to examine the 3D proteome or the conformations of proteins in their in vivo context.
OBJECTIVES: The primary objective of this work is to develop methods to measure the "structures" or confirmations of protein in the in vivo environment and to apply them to common diseases.
METHODS: We’ve developed a strategy to measure the surface accessibility of proteins in vivo that provides information about protein conformations and does so in a quantitative manner.
RESULTS: This method has been used to study protein misfolding diseases. This method has been applied to WT and mutant DF508 CFTR to examine structural changes induced by the mutation. A significant change has been observed at a critical interface between the NBD1 and NBD2 domains. This method is also being applied in Alzheimer's disease (AD)and Lewy body disease (LBD) to measure extent of conformational changes to proteins. This method is applied to AD and LBD patient brain tissue lysates and extensive protein comformational changes are observed.
CONCLUSIONS: Substantial changes beyond misfolded aBeta and Tau are observed and based on the molecular changes observed it is difficult to distinguish at the molecular level between advanced AD and LBD suggesting in neurodegenerative misfolding diseases the collapse of proteostasis has a similar endpoint. The studies of CFTR show a critical interface is disrupted between WT and DF508.
|Board Member||yes||Integrated Proteomics|
|IP Royalty||yes||University of Washington|
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