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首页> 外文期刊>Journal of Molecular Biology >Self-association of the transmembrane domain of an anthrax toxin receptor
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Self-association of the transmembrane domain of an anthrax toxin receptor

机译：炭疽毒素受体跨膜结构域的自缔合

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摘要

Protective antigen (PA), lethal factor (LF) and edema factor (EF) are secreted individually by Bacillus anthracis. These components of anthrax toxin must then assemble into complexes to intoxicate mammalian cells. Toxin assembly it-vitiates when molecules of PA bind mammalian receptors ANTXR1/2 and are cleaved by surface proteases into 20 kDa and 63 kDa fragments. After PA(20) dissociates, receptor-bound PA(63) homo-oligomerizes into heptamers. Oligomeric PA(63) binds EF and LF and these complexes are internalized into an acidic compartment where the two enzymatic components are translocated across the membrane by a channel formed by heptameric PA(63). Since oligomerization of PA(63) is required to bind and translocate the enzymatic components, we sought to determine whether interactions between toxin receptors could facilitate the assembly process. In the present work, we performed a co-immunoprecipitation experiment to demonstrate that ANTXR1 is oligomeric in mammalian cells. Computer modeling predicted the self-association of the ANTXR1 transmembrane domain and we detected oligomerization of ANTXR1 transmembrane domain peptides in the membrane-mimetic environment of SDS micelles using fluorescence resonance energy transfer. Furthermore, the ANTXR1 transmembrane domain mediated oligomerization of a reporter protein construct in a bacterial membrane. In both assays, mutations that disrupted the interaction were consistent with the interaction being mediated through an asymmetric binding interface. Mutations that impaired self-association of the transmembrane domain reduced the rate of PA(63) heptamer formation on the mammalian cell surface. Our findings indicate that ANTXR1 transmembrane domains self-associate and that these interactions may stabilize intermediate oligomerization states of ANTXR1-PA(63) complexes. (c) 2006 Elsevier Ltd. All rights reserved.
机译：炭疽芽孢杆菌分别分泌保护性抗原（PA），致死因子（LF）和水肿因子（EF）。然后，炭疽毒素的这些成分必须组装成复合物以使哺乳动物细胞中毒。当PA分子结合哺乳动物受体ANTXR1 / 2并被表面蛋白酶切割成20 kDa和63 kDa片段时，毒素组装就消失了。 PA（20）解离后，受体结合的PA（63）均聚为七聚体。寡聚PA（63）结合EF和LF，这些复合物被内化到一个酸性隔室中，其中两个酶成分通过由七聚PA（63）形成的通道跨膜移位。由于需要PA（63）的低聚才能结合和转运酶成分，因此我们试图确定毒素受体之间的相互作用是否可以促进组装过程。在本工作中，我们进行了免疫共沉淀实验，以证明ANTXR1在哺乳动物细胞中是寡聚的。计算机建模预测了ANTXR1跨膜结构域的自缔合，我们利用荧光共振能量转移在SDS胶束的膜模拟环境中检测到了ANTXR1跨膜结构域肽的寡聚。此外，ANTXR1跨膜结构域介导了细菌膜中报道蛋白构建物的寡聚。在这两种测定中，破坏相互作用的突变与通过不对称结合界面介导的相互作用一致。损害跨膜域的自缔合的突变降低了哺乳动物细胞表面上PA（63）七聚体形成的速率。我们的发现表明ANTXR1跨膜域域自相关，并且这些相互作用可能稳定ANTXR1-PA（63）配合物的中间低聚状态。 （c）2006 Elsevier Ltd.保留所有权利。

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