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Project

Bcl-2/IP3R channel structural dynamics underlying complex formation, function and disease (BInamics)

Anti-apoptotic Bcl-2 proteins not only act the mitochondria where they prevent the release of pro-cell death factors but also function at the endoplasmic reticulum (ER), the organelle that serves as the main calcium-storage site in mammalian cells. At the ER, Bcl-2, via its “BH4 domain”, directly inhibits the IP3 receptor, a large calcium-release channel, preventing mitochondrial Ca2+ overload and thus cell death to occur. Previous studies indicated that Bcl-2’s “BH4 domain” targets two regions in the IP3R channel. Recent cryoEM studies revealed that these Bcl-2-binding sites are located on the top of the channel structure, in principle out of reach for Bcl-2’s BH4 domain. Thus, it is not clear how Bcl-2, being a “dwarf protein”, through its BH4 domain can inhibit IP3R channels, giant channels. Using an interdisciplinary approach combining biophysics, biochemistry & cell biology with structural dynamics of proteins (BInamics), we aim to unravel the mechanisms by which Bcl-2 controls IP3Rs activity. Moreover, phosphorylation and disease-associated mutations, including Bcl-2 mutations that recently emerged in leukemia patients who were under prolonged venetoclax treatment, are present in Bcl-2, but their impact on Bcl-2’s properties to modulate IP3R function remain unknown. Through BInamics, we aim to elucidate their impact on IP3R/Bcl-2 complexes.

Date:1 Jan 2022 →  Today
Keywords:Bcl-2/IP3R channel
Disciplines:Molecular biophysics, Proteins, Cell signalling, Cell death, Intracellular compartments and transport