Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1
Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1
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DOI：
10.1016/j.jmb.2008.05.071
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发表时间：
2008-07-25
影响因子：
5.6
通讯作者：
Hinds, Mark G.
中科院分区：
文献类型：
--
作者：
Day, Catherine L.;Smits, Callum;Hinds, Mark G.
B细胞淋巴瘤-2（Bcl-2）家族中的促存活蛋白对其诱导细胞死亡的仅BH 3拮抗剂具有确定的特异性谱。髓样细胞白血病-1（Mcl-1）与Noxa和Puma（两种受肿瘤抑制因子p53调控的蛋白质）的BH 3结构域复合的溶液结构表明，它们在Mcl-1的相同疏水沟中结合为两亲性α-螺旋，使用保守残基进行结合。用量热法测定了Noxa、Puma及Bmf、Bim、Bid和巴克的BH 3结构域与Mcl-1相互作用的热力学参数。这些非结构化的BH 3结构域以跨越3个数量级的亲和力结合Mcl-1，并且结合是一个热力学驱动和熵-焓补偿的过程。Noxa的丙氨酸扫描分析表明，与Mcl-1相互作用仅需要残基的子集，并且这些残基定位于限定BH 3结构域的短的高度保守的序列基序。Mcl-1：BH 3复合物的化学位移作图表明，Mcl-1以类似的方式接合所有BH 3配体，并且除了结合位点附近的变化之外，小分子范围的结构调整还适应配体结合。我们的研究表明，非结构化肽，如BH 3结构域，表现得像它们的结构化对应物，并且可以在一个依赖性驱动的过程中紧密地和选择性地结合。(C)2008爱思唯尔有限公司保留所有权利。
Pro-survival proteins in the B-cell lymphoma-2 (Bcl-2) family have a defined specificity profile for their cell death-inducing BH3-only antagonists. Solution structures of myeloid cell leukaemia-1 (Mcl-1) in complex with the BH3 domains from Noxa and Puma, two proteins regulated by the tumour suppressor p53, show that they bind as amphipathic alpha-helices in the same hydrophobic groove of Mcl-1, using conserved residues for binding. Thermodynamic parameters for the interaction of Noxa, Puma and the related BH3 domains of Bmf, Bim, Bid and Bak with Mcl-1 were determined by calorimetry. These unstructured BH3 domains bind Mcl-1 with affinities that span 3 orders of magnitude, and binding is an enthalpically driven and entropy-enthalpy-compensated process. Alanine scanning analysis of Noxa demonstrated that only a subset of residues is required for interaction with Mcl-1, and these residues are localised to a short highly conserved sequence motif that defines the BH3 domain. Chemical shift mapping of Mcl-1:BH3 complexes showed that Mcl-1 engages all BH3 ligands in a similar way and that, in addition to changes in the immediate vicinity of the binding site, small molecule-wide structural adjustments accommodate ligand binding. Our studies show that unstructured peptides, such as the BH3 domains, behave like their structured counterparts and can bind tightly and selectively in an enthalpically driven process. (C) 2008 Elsevier Ltd. All rights reserved.