Myc represses the inhibition of Bax/k oligomerization in mitochondrial membranes
Zusammenfassung der Projektergebnisse
Apoptosis is one form of programmed cell death and is a highly complex process that requires the coordinated activation and interaction of multiple sub-programs. The key step of apoptosis is the permeabilization of the outer mitochondrial membrane (MOMP). MOMP is considered to be “the point of no return” in the apoptotic cascade and is strictly regulated by the interplay of different members of the Bcl-2 family of proteins at the mitochondrial outer membrane (MOM). Anti-apoptotic Bcl-2 family members like Bcl-2 and Bcl-XL are able to bind and sequester activated pro-apoptotic members like Bax and Bak, or sequester activating Bcl-2 proteins like c(t)Bid at the MOM, and therefore inhibit MOMP. BH3 only “sensitizers” like Bad are able to bind and inactivate anti-apoptotic members like Bcl-XL and therefore promote MOMP. The presented work is based on investigations of membrane-associated interactions of Bcl-XL with Bad, c(t)Bid and Bax, in a model liposome membrane system, using fluorescence spectroscopy techniques. The results revealed intriguing differences of the topology of membrane bound Bcl-XL depending on its binding partner at the membrane. The topology changes detected are consistent with Bcl-XL functioning as a dominant negative inhibitor of Bax. However, they suggest a novel mechanism of Bad to inhibit Bcl-XL bychanging the conformation of Bcl-XL helix 5 and 6 in a way that Bcl-XL cannot interact with activated Bax. Moreover, the results show evidence for the formation of higher order complexes containing multiple Bcl-2 member proteins that are important for Bax activation and regulation of membrane permeabilization. Taken together, the results suggest that to be maximally effective an anticancer drug designed to inhibit Bcl-XL may have to selectively inhibit the conformation of Bcl-XL that binds Bax and to address multimolecular complexes of c(t)Bid and Bad bound to Bcl-XL.
Projektbezogene Publikationen (Auswahl)
- Apoptosis: embedded in membranes. Curr Opin Cell Biol. 2010
Bogner C, Leber B, Andrews DW
- Canadian cancer conference in Toronto, October 2011. The Pro-apoptotic Bcl-2 family proteins cBid, Bad as well as activated Bax differentially regulate the Membrane topology and function of Bcl-XL
Lieven Billen and Christian Bogner, Brian Leber and David Andrews
- DGHO meeting in Hamburg,October 2014. Conformation dictates function: Membrane associated interactions of Bcl-XL with Bax, c(t)Bid and Bad
Christian Bogner, Lieven Billen, Brian Leber and David Andrews
