Structural Basis for Bc12-Regulated Mitochondrion-Dependent Apoptosis

摘要

The Bcl-2 family proteins are key regulators of programmed cell death, in health and major human diseases, including cancer. Their pro- or anti- apoptotic functions are regulated by subcellular location, as the proteins cycle between soluble and membrane-bound forms; by dimerization with other Bcl- 2 family members; by binding to other non-homologous proteins; and by formation of membrane pores that are believed to regulate apoptosis by perturbing mitochondrial physiology. The solution structures of several Bcl-2 family proteins are very similar despite their antagonistic activities, however, the structures of the membrane-associated proteins are not known and may be key to their opposing functions. The goals of this project are: (I) to determine the structures of the membrane-associated Bcl-2 proteins; and (2) to determine their mechanism of apoptosis regulation. The research strategy combines NMR structure determination in lipid environments with biological assays carried out in parallel with structure determination.