Molecular Control of Apoptosis
One key issue about the control of apoptosis is how the BH3-only proteins trigger the death programme. Studies together with David Huang have led us to propose that they act primarily by engaging pro-survival relatives (Chen et al, 2005; Willis et al, 2005; Willis et al, 2007; Uren et al, 2007), rather than by directly activating Bax and Bak as suggested by others. We think that apoptosis ensues if and only if the BH3-only proteins neutralize the pro-survival Bcl-2 relatives engaging Bak or Bax.
We are also exploring how the pro-survival proteins engage Bax and Bak and whether this occurs in healthy cells or only after apoptosis begins. We think the pro-survival proteins sequester a minor sub-population of Bax molecules with their BH3 domain exposed (Fletcher et al, 2008). We are also studying how Bax and Bak are activated: how their conformational changes are controlled, what drives Bax from the cytosol into the membranes, and how Bax and Bak form the oligomers (Dewson et al, 2008) that perforate the mitochondrial outer membrane.