To elucidate the biological role of the mitochondrial outer membrane (MOM), I propose to determine structures and functions of integral MOM protein complexes at atomic resolution, involving the three proteins VDAC, Bax and Sam. These are key elements of vital cellular functions: the regulation of bioenergetics, mitochondrial biogenesis, apoptosis and cancer. Our results will give new insights into the biology of eukaryotes and will open up new avenues for pharmaceutical applications.
My research group will pursue the following objectives:
A. Determination of the structures of the VDAC–NADH, the VDAC–cholesterol, and the VDAC–hexokinase complexes. These structures will provide the molecular basis for metabolism regulation by the voltage-dependent anion channel VDAC and for its role in the “Warburg effect”, a crucial step of cancerogenesis of most cancers.
B. Determination of the structure and insertion mechanism of the Bax transmembrane-pore and its formation and inhibition by drug candidates. The formation of the Bax pore in the MOM is the final, deadly step in mitochondrial apoptosis and the structure will thus elucidate a key regulatory element of multicellular organisms.
C. Determination of the structure and function of the sorting and assembly machinery (Sam), including its core protein, the beta-barrel protein Sam50, and its interactions with substrates. These results will explain the insertion of membrane proteins during the biogenesis of the MOM, an essential for eukaryotic life.
Structure determinations of membrane proteins are still major technical challenges and so far, with VDAC, only a single structure of an integral MOM protein is known, determined by the present author and colleagues. While bringing groundbreaking biological insights, our research will further extend the methodological approaches for membrane protein structure determination by nuclear magnetic resonance (NMR) spectroscopy to a new level.
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