Crystal structure of Bax bound to the BH3 peptide of Bim identifies important contacts for interaction.
Crystal structure of Bax bound to the BH3 peptide of Bim identifies important contacts for interaction.
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DOI：
10.1038/cddis.2015.141
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发表时间：
2015-07-09
影响因子：
9
通讯作者：
Czabotar PE
中科院分区：
文献类型：
--
作者：
Robin AY;Krishna Kumar K;Westphal D;Wardak AZ;Thompson GV;Dewson G;Colman PM;Czabotar PE
BH3-Only蛋白Bim是促凋亡效应蛋白Bax的有效直接激活剂，但其活性的结构基础仍不清楚。在这里，我们描述了BimBH3与BAXΔC26结合的多肽的晶体结构和基于结构的突变研究。与BidBH3类似，BimBH3多肽通过保守的疏水BH3残基h1-h4结合到Bax的同源表面凹槽中。然而，结构和突变数据表明，与Bid相比，Bim对其‘H0’残基激活Bax的依赖性较低，并且Bim和Bid之间的单个氨基酸差异导致Bax结合效力的五倍之差。与BAXΔC21结合的BidBH3和BaxBH3的结构相似，BimBH3与BAXΔC的复合体的结构显示出一个被BAXα1、α2、α5和α8包围的空腔。我们的结果与一个模型一致，该模型认为激活剂BH3结构域与BAX沟槽结合引发其核心结构域(α2-α5)和闩锁结构域(α6-α8)的分离，从而使其随后的二聚化和线粒体外膜的通透性。
The BH3-only protein Bim is a potent direct activator of the proapoptotic effector protein Bax, but the structural basis for its activity has remained poorly defined. Here we describe the crystal structure of the BimBH3 peptide bound to BaxΔC26 and structure-based mutagenesis studies. Similar to BidBH3, the BimBH3 peptide binds into the cognate surface groove of Bax using the conserved hydrophobic BH3 residues h1–h4. However, the structure and mutagenesis data show that Bim is less reliant compared with Bid on its ‘h0' residues for activating Bax and that a single amino-acid difference between Bim and Bid encodes a fivefold difference in Bax-binding potency. Similar to the structures of BidBH3 and BaxBH3 bound to BaxΔC21, the structure of the BimBH3 complex with BaxΔC displays a cavity surrounded by Bax α1, α2, α5 and α8. Our results are consistent with a model in which binding of an activator BH3 domain to the Bax groove initiates separation of its core (α2–α5) and latch (α6–α8) domains, enabling its subsequent dimerisation and the permeabilisation of the mitochondrial outer membrane.