Investigations of the specificity and promiscuity of receptors within the BCL‐2 protein family (971.2)

Abstract

The BCL‐2 protein homology plays a central role in regulating the intrinsic pathway of apoptosis. These proteins often hold the key to a cells decision to live or die following factors such as irreversible DNA damage. Not surprisingly, the anti‐apoptotic members of this family are over expressed in many cancers where they contribute to the formation, progression and chemo‐resistance of tumor cells. The promiscuous recognition of helical BH3 domains by the BCL‐2 class of proteins makes their exact roles in apoptosis difficult to determine and thus contribute to challenges in designing effective therapies. We seek to identify the molecular determinants of binding between the BCL‐2 homologs and their BH3 targets. Using in‐vitro translation and a luciferase based florescence assay we have examined the effects of mutations to the receptor pocket of BCL‐2 and MCL‐1 on interactions with 9 BH3 only proteins. Results from these experiments should formulate a picture of the role different members of this homology play in cell death. Moreover, these results will allow for the design of orthogonal receptor/ligand pairs, helpful for further interrogating this pathway. Grant Funding Source: Arnold and Mabel Beckman Foundation