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Structure—Function Analysis of Bcl-2 Family Proteins

Regulators of Programmed Cell Death

  • Chapter

Part of the Advances in Experimental Medicine and Biology book series (AEMB,volume 406)

Abstract

The Bcl-2 protein blocks a distal step in an evolutionarily conserved pathway for programmed cell death and apoptosis. To gain better understanding of how this protein functions, we have undertaken a structure-function analysis of this protein, focusing on domains within Bcl-2 that are required for function and for interactions with other proteins. Four conserved domains are present in Bcl-2 and several of its homologs: BH1 (residues 136–155), BH2 (187–202), BH3 (93–107) and BH4 (10–30). Deletion of the BH1, BH2, or BH4 domains of Bcl-2 abolishes its ability to suppress cell death in mammalian cells and prevents homodimerization of these mutant proteins, though these mutants can still bind to the wild-type Bcl-2 protein. These mutants also fail to bind to BAG-1 and Raf-1, two proteins that we have shown can associate with protein complexes containing Bcl-2 and which cooperate with Bcl-2 to suppress cell death. Deletion of either BH1 or BH2 nullifies the ability of Bcl-2 to: (a) suppress death in mammalian cells; (b) block Bax-induced lethality in yeast; and (c) heterodimerize with Bax. In contrast, deletion of the BH4 domain of Bcl-2 nullifies anti-apoptotic function and homodimerization, but does not impair binding to the pro-apoptotic protein Bax. Taken together, the data suggest the possibility that both Bcl-2/Bcl-2 homodimerization and Bcl-2/Bax heterodimerization are necessary but insufficient for the anti-apoptotic function of the Bcl-2 protein. Homodimerization of Bcl-2 with itself involves a head-to-tail interaction, in which an N-terminal domain where BH4 resides interacts with the more distal region of Bcl-2 where BH1, BH2, and BH3 are located. In contrast, Bcl-2/Bax heterodimerization involves a tail-to-tail interaction, that requires the portion of Bcl-2 where BH1, BH2, and BH3 reside and a central region in Bax where the BH3 domain is located. The BH3 domain of Bax is also required for Bax/Bax homodimerization and pro-apoptotic function in both yeast and mammalian cells. Thus, Bcl-2 may suppress cell death at least in part by binding to Bax via the BH3 domain and thereby preventing formation of Bax/Bax homodimers. Further studies however are required to delineate the full significance of Bcl-2/Bcl-2, Bcl-2/Bax, and Bax/Bax dimers and the biochemical mechanisms by which Bcl-2 family proteins ultimately control cell life and death.

Keywords

  • Programme Cell Death
  • African Swine Fever Virus
  • Promote Cell Death
  • Autoimmune Lymphoproliferative Syndrome
  • Suppress Cell Death

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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© 1996 Springer Science+Business Media New York

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Reed, J.C., Zha, H., Aime-Sempe, C., Takayama, S., Wang, HG. (1996). Structure—Function Analysis of Bcl-2 Family Proteins. In: Gupta, S., Cohen, J.J. (eds) Mechanisms of Lymphocyte Activation and Immune Regulation VI. Advances in Experimental Medicine and Biology, vol 406. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0274-0_10

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  • DOI: https://doi.org/10.1007/978-1-4899-0274-0_10

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