The Bax BH3 peptide H2-H3 promotes apoptosis by inhibiting Bcl-2's pore-forming and anti-Bax activities in the membrane / 生物医学工程学杂志
Journal of Biomedical Engineering
; (6): 829-835, 2009.
Article
em En
| WPRIM
| ID: wpr-294559
Biblioteca responsável:
WPRO
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.
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Assunto principal:
Fisiologia
/
Química
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Apoptose
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Proteínas Proto-Oncogênicas c-bcl-2
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Proteínas de Transporte da Membrana Mitocondrial
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Membranas Mitocondriais
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Proteína X Associada a bcl-2
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Proteína Killer-Antagonista Homóloga a bcl-2
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Proteína Agonista de Morte Celular de Domínio Interatuante com BH3
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Proteínas de Membrana
Limite:
Humans
Idioma:
En
Revista:
Journal of Biomedical Engineering
Ano de publicação:
2009
Tipo de documento:
Article