Structure and function of the Bcl-2 protein family
Crystal structures of Mcl-1 bound to the BH3 domains of the BH3-only proteins Bim and Noxa have been determined, together with an NMR structure for the Noxa complex. The structure, and subsequent mutagenesis analysis, has shed light on the observation that Mcl-1 protein levels in the cell are stabilized through interaction with Bim but Mcl-1 is targeted for degradation when complexed with Noxa. A characteristic sequence in the C-terminal part of the Noxa BH3 domain has been implicated in triggering the degradation of Mcl-1. Through the use of a novel BH3 sequence derived from the BH3 domain of Bim, we have shown that cell death can be initiated even when Mcl-1 protein levels are high, provided that Mcl-1 is prevented from engaging the pro-apoptotic Bcl-2 family member Bak.
Our structure of the Bcl-2 antagonist ABT-737 bound to Bcl-xL has revealed some unexpected features of the complex, and suggested why the compound is unable to engage the Bcl-2 family member Mcl-1. We have recently derived a first ever image of a so-called ‘foldamer’, a peptide containing a mixture of alpha- and beta- amino acids, bound to its protein target, in this case Bcl-xL. The structure confirms the design features of the foldamer and supports the notion that such peptides could be tailored to bind a number of important drug targets.
Ongoing studies are directed at further understanding the interactions between pro-survival and pro-apoptotic members of the Bcl-2 family as a basis for discovering compounds that are better able to trigger the death of unwanted (e.g. tumor) cells.
