The Bax BH3 peptide H2-H3 promotes apoptosis by inhibiting Bcl-2's pore-forming and anti-Bax activities in the membrane.
- Author:
Jun PENG
1
;
Suzanne M LAPOLLA
;
Zhi ZHANG
;
Jialing LIN
Author Information
1. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Boulevard, Oklahoma City, OK 73190, USA. pjunlab@hotmail.com
- Publication Type:Journal Article
- MeSH:
Apoptosis;
physiology;
BH3 Interacting Domain Death Agonist Protein;
chemistry;
Humans;
Membrane Proteins;
chemistry;
metabolism;
Mitochondrial Membrane Transport Proteins;
Mitochondrial Membranes;
metabolism;
Proto-Oncogene Proteins c-bcl-2;
antagonists & inhibitors;
chemistry;
bcl-2 Homologous Antagonist-Killer Protein;
chemistry;
bcl-2-Associated X Protein;
chemistry
- From:
Journal of Biomedical Engineering
2009;26(4):829-835
- CountryChina
- Language:English
-
Abstract:
Pore-formation and protein-protein interactions are considered to play critical roles in the regulation of apoptosis by Bcl-2 family proteins. During the initiation of apoptosis, the anti-apoptotic Bcl-2 and the pro-apoptotic Bax form different pores to regulate the permeability of mitochondrial outer membrane, playing their opposite functions. Overexpression of Bcl-2 has been found in various cancer cells, therefore it is gaining widespread interest to discover small molecules to compromise Bcl-2 function for anti-cancer treatment. Since Bax binds to Bcl-2's hydrophobic groove via its BH3 domain (composed of helices 2 and 3), by which their functions are inhibited each other, the H2-H3 peptide that contains the functional BH3 domain of Bax has been considered as a potential Bcl-2 antagonist. We recently reported that Bax peptide H2-H3 promotes cell death by inducing Bax-mediated cytochrome c release and by antagonizing Bcl-2's inhibitory effect on Bax. However, the mechanism of how H2-H3 inhibits the anti-apoptotic activity of Bcl-2 remains poorly understood. To address this question, we reconstituted the Bcl-2 or Bax pore-forming process in vitro. We found that H2-H3 inhibited Bcl-2's pore formation and neutralized Bcl-2's inhibitory effect on Bax pore formation in the membrane, whereas the mutant H2-H3 peptide that does not induce apoptosis in cells was shown to have no effect on Bcl-2's activities. Thus, inhibiting Bcl-2's pore-forming and anti-Bax activities in the membrane is strongly correlated with H2-H3's pro-apoptosis function in cells.