The intramembrane protease gamma-secretase is a current target of therapeutic intervention in Alzheimer's disease and cancer. Our primary objective is to expand methods for in vitro studies of the intramembrane proteases (IMPs) with the development of a microsphere-supported biomembrane (proteolipobead) platform. Despite extensive studies, the precise reaction mechanisms of the intramembrane proteases remain to be elucidated.A critical barrier to further progress in the study of gamma-secretase is that such bulk systems do not allow for the direct in situ quantification of enzyme, substrates, or inhibitors or their relative distributions within the structures under assay. We have expanded in vitro models of gamma-secretase to include microsphere- supported biomembranes. Using 3D imaging and flow cytometry, we will present findings from i) direct measurements of substrate and gamma-secretase loading within supported biomembranes, ii) the localization and quantification of enzyme:substrate and enzyme:inhibitor complexes within supported biomembranes, and iii) comparisons of stability of tether-supported assays.

Stabilized proteolipobead microenvironments for the functional analysis and drug screening of the cancer and Alzheimer's disease drug target gamma-secretase

245th National Meeting (2013)

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