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Understanding how the Bcl-2 interactome contributes to apoptotic sensitivity
[Thesis]. Manchester, UK: The University of Manchester; 2019.
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Abstract
Apoptotic sensitivity between individual cells within a population is varied and the molecular basis of this variation is unclear. Bcl-2 family proteins are the central regulators of apoptosis at mitochondria, with interactions between pro- and anti- apoptotic family members dictating the life or death decision of a cell. Bcl-2 proteins are in equilibrium between mitochondria and cytosol, which shifts to a more mitochondrial state as cells move closer to their apoptotic threshold, termed mitochondrial priming. Heterogeneity in anti-apoptotic Bcl-2 protein dynamics in live cells is predictive of priming within cell populations. What regulates the changes in interactions between pro- and anti-apoptotic proteins in a healthy cell compared to a cell that is primed to die is complex. Using live cell imaging techniques, we show that BH3-mimetics such as ABT-737 do not fully recapitulate the binding of full length BH3 proteins at the outer mitochondrial membrane (OMM). What differs between these binding mechanisms is unknown, but it is likely due to full-length Bcl-2 proteins forming part of larger regulatory complexes at the OMM. Using a proximity Biotin labelling approach to determine what other factors are involved in regulating Bcl-2 protein dynamics outside of the protein family itself reveals that mitochondrial membrane proteins are likely to play a key role. Examining these interactions in more detail will improve our understanding of the causes of apoptotic heterogeneity within cell populations and may enable improved efficacy of BH3-mimetic compounds.