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Project

Bcl-2/Bcl-XL proteins as modulators of calcium signaling through IP3 receptors: from novel molecular mechanisms to implications for therapeutics

Anti-apoptotic Bcl-2 and Bcl-XL proteins, which enable malignant cell survival, emerged as critical modulators of intracellular Ca2+ signals by targeting IP3 receptors (IP3Rs). Yet, the molecular basis by which Bcl-2 and Bcl-XL affect IP3Rs remains elusive. We will combine molecular & cell biological, biophysical and imaging-based approaches to unravel fundamental aspects of IP3R regulation by Bcl-2/Bcl-XL proteins and the interplay between Ca2+ signaling and Bcl-2/Bcl-XL-inhibiting drugs. We will examine how a small protein such as Bcl-2 can inhibit the large IP3R. We also identified a novel Bcl-2-binding site in the ligand-binding domain of IP3Rs, yet the molecular determinants and relevance of this site remain unknown. We will also assess whether IP3R/Bcl-2-complex formation can be modulated by phosphorylation and proteins targeting Bcl-2. Finally, our recent work challenges the role of Bcl-XL as an IP3R sensitizer, which will be further analysed in-depth, including in Bcl-XL-dependent cancer cells.
Date:1 Oct 2019 →  30 Sep 2023
Keywords:Ca2+ signaling, IP3 receptor, Bcl-2 proteins, structure-function, therapeutics, cell death, intracellular Ca2+-release channels, cellular physiology
Disciplines:Cell physiology