Bid binding to negatively charged phospholipids may not be required for its pro-apoptotic activity in vivo
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- 作者：Anna Manara ; Jennefer Lindsay ; Marta Marchioretto ; Aless ; ra Astegno ; Andrew P. Gilmore ; Mauro Degli Esposti ; Massimo Crimi
- 关键词：Apoptosis ; Bid ; Mitochondria ; Phospholipids ; Caspase 8
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
- 出版年：2009
- 出版时间：October 2009
- 年：2009
- 卷：1791
- 期：10
- 页码：997-1010
- 全文大小：1958 K
文摘
Bid is a ubiquitous pro-apoptotic member of the Bcl-2 family that has been involved in a variety of pathways of cell death. Unique among pro-apoptotic proteins, Bid is activated after cleavage by the apical caspases of the extrinsic pathway; subsequently it moves to mitochondria, where it promotes the release of apoptogenic proteins in concert with other Bcl-2 family proteins like Bak. Diverse factors appear to modulate the pro-apoptotic action of Bid, from its avid binding to mitochondrial lipids (in particular, cardiolipin) to multiple phosphorylations at sites that can modulate its caspase cleavage. This work addresses the question of how the lipid interactions of Bid that are evident in vitro actually impact on its pro-apoptotic action within cells. Using site-directed mutagenesis, we identified mutations that reduced mouse Bid lipid binding in vitro. Mutation of the conserved residue Lys157 specifically decreased the binding to negatively charged lipids related to cardiolipin and additionally affected the rate of caspase cleavage. However, this lipid-binding mutant had no discernable effect on Bid pro-apoptotic function in vivo. The results are interpreted in relation to an underlying interaction of Bid with lysophosphatidylcholine, which is not disrupted in any mutant retaining pro-apoptotic function both in vitro and in vivo.