ArticlePloS one2013
Alpha-helical destabilization of the Bcl-2-BH4-domain peptide abolishes its ability to inhibit the IP3 receptor.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 29 citations in OpenAlex.
- Bok binds to a largely disordered loop in the coupling domain of type 1 inositol 1,4,5-trisphosphate receptor.Biochemical and biophysical research communications · 2021Article
- Bcl-2-Protein Family as Modulators of IPCold Spring Harbor perspectives in biology · 2020Review
- Clinical Review: Navitoclax as a Pro-Apoptotic and Anti-Fibrotic Agent.Frontiers in pharmacology · 2020Review
- Bcl-2 and IPCellular and molecular life sciences : CMLS · 2019Article
- Creating a New Cancer Therapeutic Agent by Targeting the Interaction between Bcl-2 and IPCold Spring Harbor perspectives in biology · 2019Review
- Targeting Bcl-2-IPBiochimica et biophysica acta. Molecular cell research · 2018Review
- BH4 domain peptides derived from Bcl-2/Bcl-XL as novel tools against acute pancreatitis.Cell death discovery · 2018Article
- Organelle membrane derived patches: reshaping classical methods for new targets.Scientific reports · 2017Article
- Review
- The trans-membrane domain of Bcl-2α, but not its hydrophobic cleft, is a critical determinant for efficient IP3 receptor inhibition.Oncotarget · 2016Article
- The Stability and Expression Level of Bok Are Governed by Binding to Inositol 1,4,5-Trisphosphate Receptors.The Journal of biological chemistry · 2016Article
- Synergistic killing of human small cell lung cancer cells by the Bcl-2-inositol 1,4,5-trisphosphate receptor disruptor BIRD-2 and the BH3-mimetic ABT-263.Cell death & disease · 2015Article
- Emerging understanding of Bcl-2 biology: Implications for neoplastic progression and treatment.Biochimica et biophysica acta · 2015Review
- Inhibition of Pro-apoptotic BAX by a noncanonical interaction mechanism.Molecular cell · 2015Article
Corrections and comments
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Authors and funding
13 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The anti-apoptotic Bcl-2 protein is the founding member and namesake of the Bcl-2-protein family. It has recently been demonstrated that Bcl-2, apart from its anti-apoptotic role at mitochondrial membranes, can also directly interact with the inositol 1,4,5-trisphosphate receptor (IP3R), the primary Ca(2+)-release channel in the endoplasmic reticulum (ER). Bcl-2 can thereby reduce pro-apoptotic IP3R-mediated Ca(2+) release from the ER. Moreover, the Bcl-2 homology domain 4 (Bcl-2-BH4) has been identified as essential and sufficient for this IP3R-mediated anti-apoptotic activity. In the present study, we investigated whether the reported inhibitory effect of a Bcl-2-BH4 peptide on the IP 3R1 was related to the distinctive α-helical conformation of the BH4 domain peptide. We therefore designed a peptide with two glycine "hinges" replacing residues I14 and V15, of the wild-type Bcl-2-BH4 domain (Bcl-2-BH4-IV/GG). By comparing the structural and functional properties of the Bcl-2-BH4-IV/GG peptide with its native counterpart, we found that the variant contained reduced α-helicity, neither bound nor inhibited the IP 3R1 channel, and in turn lost its anti-apoptotic effect. Similar results were obtained with other substitutions in Bcl-2-BH4 that destabilized the α-helix with concomitant loss of IP3R inhibition. These results provide new insights for the further development of Bcl-2-BH4-derived peptides as specific inhibitors of the IP3R with significant pharmacological implications.
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