Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Apr;70(7):1171-83.
doi: 10.1007/s00018-012-1118-y. Epub 2012 Sep 6.

The selective BH4-domain biology of Bcl-2-family members: IP3Rs and beyond

Giovanni Monaco  1 , Tim Vervliet, Haidar Akl, Geert Bultynck
Affiliations
Review

The selective BH4-domain biology of Bcl-2-family members: IP3Rs and beyond

Giovanni Monaco et al. Cell Mol Life Sci. 2013 Apr.

Abstract

Anti-apoptotic Bcl-2-family members not only neutralize pro-apoptotic proteins but also directly regulate intracellular Ca(2+) signaling from the endoplasmic reticulum (ER), critically controlling cellular health, survival, and death initiation. Furthermore, distinct Bcl-2-family members may selectively regulate inositol 1,4,5-trisphosphate receptor (IP3R): Bcl-2 likely acts as an endogenous inhibitor of the IP3R, preventing pro-apoptotic Ca(2+) transients, while Bcl-XL likely acts as an endogenous IP3R-sensitizing protein promoting pro-survival Ca(2+) oscillations. Furthermore, distinct functional domains in Bcl-2 and Bcl-XL may underlie the divergence in IP3R regulation. The Bcl-2 homology (BH) 4 domain, which targets the central modulatory domain of the IP3R, is likely to be Bcl-2's determining factor. In contrast, the hydrophobic cleft targets the C-terminal Ca(2+)-channel tail and might be more crucial for Bcl-XL's function. Furthermore, one amino acid critically different in the sequence of Bcl-2's and Bcl-XL's BH4 domains underpins their selective effect on Ca(2+) signaling and distinct biological properties of Bcl-2 versus Bcl-XL. This difference is evolutionary conserved across five classes of vertebrates and may represent a fundamental divergence in their biological function. Moreover, these insights open novel avenues to selectively suppress malignant Bcl-2 function in cancer cells by targeting its BH4 domain, while maintaining essential Bcl-XL functions in normal cells. Thus, IP3R-derived molecules that mimic the BH4 domain's binding site on the IP3R may function synergistically with BH3-mimetic molecules selectivity suppressing Bcl-2's proto-oncogenic activity. Finally, a more general role for the BH4 domain on IP3Rs, rather than solely anti-apoptotic, may not be excluded as part of a complex network of molecular interactions.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Differential regulation of IP3R channels by Bcl-2 versus Bcl-XL. The Ca2+-flux properties of IP3R are thought to be critically controlled by Bcl-2-family members to promote cell survival or protect against cell death. We hypothesize that distinct Bcl-2-family members target distinct IP3R domains. In this paradigm, Bcl-2 through its BH4 domain may primarily target the central, modulatory domain of the IP3R, thereby reducing large global pro-apoptotic Ca2+ transients (left), while Bcl-XL through its hydrophobic cleft (HC) or another domain may primarily target the C-terminal tail of the IP3R close to the channel pore, thereby increasing IP3R sensitivity to basal IP3 levels and promoting pro-survival Ca2+ oscillations (right). It should be noted that the C-terminal domain of IP3Rs has been proposed to harbors BH3-like domains and may also recruit Bcl-2. In addition, there is increasing evidence that other Bcl-2-family members may target IP3Rs, like NrZ, the zebrafish homologue of Bcl-2L10, through its BH4 domain and Mcl-1 through its hydrophobic cleft (HC) or another domain may primarily target the C-terminal tail of the IP3R close to the channel pore
Fig. 2
Fig. 2
A representation of the overlapping Bcl-2 and Bcl-XL structures. Their respective BH4 domains (blue for Bcl-2, orange for Bcl-XL) have been indicated together with the critical difference between Bcl-2 (Lys17) and Bcl-XL (Asp11), which determines the ability of Bcl-2, but not of Bcl-XL, to interact with the central, modulatory domain of the IP3R
Fig. 3
Fig. 3
Sequence alignment of the BH4 domain of different Bcl-2 and Bcl-XL homologues in the different classes of vertebrates. Bcl-2 and Bcl-XL homologues were obtained from the DeathBase [152]. The number between brackets indicates the accession number of the protein database of the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/protein). This analysis reveals that the amino acid Lys17 in human Bcl-2 is conserved as a positively charged residue during evolution. The amino acid Asp11 in human Bcl-XL also seems conserved as a negatively charged residue during evolution, although Xenopus Bcl-XL contains a Lys and zebrafish Bcl-XL contains a Phe in the corresponding position. The positively charged (red) and negatively charged (blue) amino acids are depicted in color. The conserved critical Lys residue in the Bcl-2 homologues and its corresponding residue in the Bcl-XL homologues are displayed on a gray background and are indicated by an arrow
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Chipuk JE, Green DR. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol. 2008;18:157–164. doi: 10.1016/j.tcb.2008.01.007. - DOI - PMC - PubMed
    1. Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 2009;122:437–441. doi: 10.1242/jcs.031682. - DOI - PMC - PubMed
    1. Chipuk JE, et al. The BCL-2 family reunion. Mol Cell. 2010;37:299–310. doi: 10.1016/j.molcel.2010.01.025. - DOI - PMC - PubMed
    1. Edlich F, et al. Bcl-XL retrotranslocates Bax from the mitochondria into the cytosol. Cell. 2011;145:104–116. doi: 10.1016/j.cell.2011.02.034. - DOI - PMC - PubMed
    1. Soriano ME, Scorrano L. Traveling Bax and forth from mitochondria to control apoptosis. Cell. 2011;145:15–17. doi: 10.1016/j.cell.2011.03.025. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances