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Oligomerization of membrane-bound Bcl-2 is involved in its pore formation induced by tBid

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Abstract

Both pro-apoptotic Bax and anti-apoptotic Bcl-2 are structurally homologous to the pore-forming domain of bacterial toxins. Bax proteins oligomerize in the mitochondrial outer membranes forming pores that release cytochrome c from the mitochondrial intermembrane space. Bcl-2 proteins also form pores that, however, are much smaller than the Bax pore. It is unknown whether Bcl-2 forms monomeric or oligomeric pores. Here, we characterized the Bcl-2 pore formation in liposomes using biophysical and biochemical techniques. The results show that the Bcl-2 pore enlarges as the concentration of Bcl-2 increases, suggesting that the pore is formed by Bcl-2 oligomers. As expected from oligomerization-mediated pore-formation, the small pores are formed earlier than the large ones. Bcl-2 oligomers form pores faster than the monomer, indicating that the oligomerization constitutes an intermediate step of the pore formation. A Bcl-2 mutant with higher affinity for oligomerization forms pores faster than wild type Bcl-2. Bcl-2 oligomers were detected in the liposomal membranes under conditions that Bcl-2 forms pores, and the extent of oligomerization was positively correlated with the pore-forming activity. Therefore, Bcl-2 oligomerizes in membranes forming pores, but the extent of oligomerization and the size of the resulting pores are much smaller than that of Bax, supporting the model that Bcl-2 is a defective Bax.

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Acknowledgments

This work was supported in part by the grant GM062964 from the National Institutes of Health to J. L.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Boulevard, Oklahoma City, OK, 73126, USA

    Jun Peng, Jingzhen Ding, Chibing Tan, Bruce Baggenstoss, Zhi Zhang, Suzanne M. Lapolla & Jialing Lin

  2. Academy of Integrative Medicine, Fuzhou, Fujian, 350108, China

    Jun Peng

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  1. Jun Peng
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  2. Jingzhen Ding
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Correspondence to Jialing Lin.

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Peng, J., Ding, J., Tan, C. et al. Oligomerization of membrane-bound Bcl-2 is involved in its pore formation induced by tBid. Apoptosis 14, 1145–1153 (2009). https://doi.org/10.1007/s10495-009-0389-8

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