期刊
CELL DEATH AND DIFFERENTIATION
卷 9, 期 11, 页码 1240-1247出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4401097
关键词
BAD; apoptosis; Bcl-2 family; BH3 domain; phosphorylation
The BH3-only protein BAD binds to Bcl-2 family proteins through its BH3 domain. Recent studies suggest that BAD binds to both Bcl-2 and Bcl-X-L, however mediates its proapoptotic functions through inhibition of Bcl-X-L, but not Bcl-2. In this paper we addressed this issue using a BAD mutant within the BH3 domain, by substitution of Asp 119 with Gly (BAD(D119G)), which selectively abrogates an ability to interact with Bcl-2. Confocal microscopy revealed that mutation of BAD at D119 does not affect BAD targeting to the mitochondrial membrane in serum-starved COS-7 cells. However, co-precipitation assays indicated that, whereas wild-type BAD (BADwt) directly interacts with Bcl-2 and Bcl-X-L, BAD(D119G) interacts only with Bcl-X-L. Nevertheless both BADwt and BAD(D119G) could introduce apoptosis and diminish the anti-apoptotic effect of Bcl-2 and Bcl-X-L in a similar manner in a co-transfection assay. These data thus suggest that Asp119 is a crucial site within the BH3 domain of BAD for interaction of BAD with Bcl-2, but is dispensable for the interaction of BAD with Bcl-X-L, for its targeting to mitochondria, and most importantly, for its pro-apoptotic functions. Thus, we confirm that neutralization of Bcl-2 function is marginal for BAD-mediated apoptosis.
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