Characterizing BCL-2 family protein domains in membranes:insertion, interaction and apoptotic modulation roles

Apoptosis (programmed cell death) is executed by strongly regulated pathways to remove infected, damaged or ectopic cells. However, Apoptosis dysregulation is at the root of a variety of diseases. The BCL-2 family of proteins are involved in sensing various cellular stress linked to mitochondrial outer membrane permeabilization (MOMP). Upon the induction of apoptosis, the integrity of the MOM is breached, resulting in the release of cytochrome c and other proteins into the cytoplasm. A series of protein-protein and protein-membrane interactions are thus activated and controlled in the membranes. Up to now, several studies reveal that these interactions are lead by the commonly shared BH3 domain (BCL-2 Homology domain) but characterizing their membrane interaction properties will further our understanding on the mechanistic role of the BCL-2 family of proteins in the MOMP and the complexity of regulating apoptosis. The putative TM domains of anti- apoptotic (Bcl-2, Bcl-xL, Bcl-w and Mcl-1), pro-apoptotic (Bax, Bak) and BH3-only members have been characterized for their structure and interaction properties in a membrane context. The roles of these C-terminal putative TM domains in MOMP and apoptosis were further investigated on liposomes, isolated mitochondrial and whole cell. Overall the results demonstrate the capability of BCL-2 TMDs to establish an interaction network in the MOM. Furthermore, some of these BCL-2 TMDs can destabilize the MOM integrity, promoting cytochrome c release and apoptosis.