Reversible membrane interaction of BAD requires two C-terminal lipid binding domains in conjunction with 14-3-3 protein binding

被引:52
|
作者
Hekman, Mirko
Albert, Stefan
Galmiche, Antoine
Rennefahrt, Ulrike E. E.
Fueller, Jochen
Fischer, Andreas
Puehringer, Dirk
Wiese, Stefan
Rapp, Ulf R.
机构
[1] Univ Wurzburg, Inst Med Radiat & Cell Res, D-97078 Wurzburg, Germany
[2] Univ Wurzburg, Inst Clin Neurobiol, D-97078 Wurzburg, Germany
关键词
DEATH AGONIST BAD; CELL-DEATH; MITOCHONDRIAL-MEMBRANE; MODEL MEMBRANES; BCL-2; PROTEINS; KINASE RAF-1; PHOSPHORYLATION; SURVIVAL; RAFTS; APOPTOSIS;
D O I
10.1074/jbc.M600292200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
BAD is a Bcl-2 homology domain 3 (BH3)-only proapoptotic member of the Bcl-2 protein family that is regulated by phosphorylation in response to survival factors. Binding of BAD to mitochondria is thought to be exclusively mediated by its BH3 domain. We show here that BAD binds to lipids with high affinities, predominantly to negatively charged phospholipids, such as phosphatidylserine, phosphatidic acid, and cardiolipin, as well as to cholesterol-rich liposomes. Two lipid binding domains (LBD1 and LBD2) with different binding preferences were identified, both located in the C-terminal part of the BAD protein. BAD facilitates membrane translocation of Bcl-X-L in a process that requires LBD2. Integrity of LBD1 and LBD2 is also required for proapoptotic activity in vivo. Phosphorylation of BAD does not affect membrane binding but renders BAD susceptible to membrane extraction by 14-3-3 proteins. BAD can be removed efficiently by 14-3-3 zeta, -eta, -tau and less efficiently by other 14-3-3 isoforms. The assembled BAD center dot 14-3-3 complex exhibited high affinity for cholesterol-rich liposomes but low affinity for mitochondrial membranes. We conclude that BAD is a membrane-associated protein that has the hallmarks of a receptor rather than a ligand. Lipid binding is essential for the proapoptotic function of BAD in vivo. The data support a model in which BAD shuttles in a phosphorylation-dependent manner between mitochondria and other membranes and where 14-3-3 is a key regulator of this relocation. The dynamic interaction of BAD with membranes is tied to activation and membrane translocation of Bcl-X-L.
引用
收藏
页码:17321 / 17336
页数:16
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