Death receptor signaling
We are refining our first generation kinetic models to incorporate more of the biochemistry controlling the onset of mitochondrial membrane polarization (MOMP) and test some key model-based predictions. These include the idea that the physical organization of Bcl-2 family proteins in space is critical for correct snap-action control of MOMP, and the idea that XIAP plays an essential role as an E3 ubiquitin ligase during the extended pre-MOMP delay phase. We are also examining whether the generation of “partially-dead cells” by failure of snap action switching leads to genomic instability.
A second project is to incorporate high resolution structural information into kinetic models of interactions among Bcl-2 family proteins. We expect that structural insight and protein design will powerfully complement kinetic modeling. Finally, we are extending our current work on extrinsic cell death to include pathways of intrinsic cell death, particularly those activated by DNA damage.