Abstract
Abstract BCL-2 family proteins are key regulators of apoptotic and other signaling pathways in health and disease. Discrete amphipathic alpha-helices embedded within the protein infrastructure are essential interaction motifs that can inhibit or activate their physiologic targets. The canonical complex between a pro-apoptotic BCL-2 homology domain 3 (BH3) helix and a surface groove on anti-apoptotic members portrayed a molecular wrestling match between pro- and anti-apoptotic signals. If anti-apoptotic grooves are sufficient in number to bind and sequester the pro-apoptotic BH3 signals, cell survival prevails. In contrast, if the capacity to withstand pro-apoptotic assault is breached, cell death ensues. Not only did this protein interaction paradigm provide a mechanism for apoptotic regulation, but it also informed the development of drugs to reactivate cell death through targeted inhibition of anti-apoptotic BH3-binding pockets. Given the critical roles of amphipathic alpha-helices in mediating signal transduction, we advanced all-hydrocarbon stapling to refold bioactive alpha-helical peptides for use as research tools and prototype therapeutics. Depending on their amino acid composition and design, “stapled peptides” have proven to be structurally stable, protease resistant, and cell permeable agents capable of interrogating and modulating protein interactions in vitro and in vivo. Here, I present our latest applications of Stabilized Alpha-Helices of BCL-2 domains (SAHBs) to dissect the canonical and noncanonical interactions that directly regulate the functional activity of BCL-2 family proteins and their targets. Our findings broaden the opportunities to pharmacologically modulate cell death and other physiologic processes by revealing new protein terrain for therapeutic targeting. Citation Format: Loren D. Walensky. Dissecting the canonical and noncanonical interactions of the BCL-2 family for therapeutic benefit. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY37-01. doi:10.1158/1538-7445.AM2014-SY37-01
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