The BH3 domain of Bcl-x(S) is required for inhibition of the antiapoptotic function of Bcl-x(L).

Chang BS, Kelekar A, Harris MH, Harlan JE, Fesik SW, Thompson CB
Mol Cell Biol. 1999 19 (10): 6673-81

PMID: 10490606 · PMCID: PMC84651 · DOI:10.1128/mcb.19.10.6673

bcl-x is a member of the bcl-2 family of genes. The major protein product, Bcl-x(L), is a 233-amino-acid protein which has antiapoptotic properties. In contrast, one of the alternatively spliced transcripts of the bcl-x gene codes for the protein Bcl-x(S), which lacks 63 amino acids present in Bcl-x(L) and has proapoptotic activity. Unlike other proapoptotic Bcl-2 family members, such as Bax and Bak, Bcl-x(S) does not seem to induce cell death in the absence of an additional death signal. However, Bcl-x(S) does interfere with the ability of Bcl-x(L) to antagonize Bax-induced death in transiently transfected 293 cells. Mutational analysis of Bcl-x(S) was conducted to identify the domains necessary to mediate its proapoptotic phenotype. Deletion mutants of Bcl-x(S) which still contained an intact BH3 domain retained the ability to inhibit survival through antagonism of Bcl-x(L). Bcl-x(S) was able to form heterodimers with Bcl-x(L) in mammalian cells, and its ability to inhibit survival correlated with the ability to heterodimerize with Bcl-x(L). Deletion mutants of Bax and Bcl-2, which lacked BH1 and BH2 domains but contained a BH3 domain, were able to antagonize the survival effect conferred by Bcl-x(L). The results suggest that BH3 domains from both pro- and antiapoptotic Bcl-2 family members, while lacking an intrinsic ability to promote programmed cell death, can be potent inhibitors of Bcl-x(L) survival function.

MeSH Terms (13)

Apoptosis bcl-2-Associated X Protein bcl-X Protein Binding Sites Dimerization Humans Mutation Phenotype Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Sequence Deletion

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