The mitochondrial permeability transition pore
The mitochondrial permeability transition pore
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DOI：
10.1042/bss0660167
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发表时间：
1999-01-01
期刊：
影响因子：
--
通讯作者：
Ward, JM
中科院分区：
文献类型：
--
作者：
Crompton, M;Virji, S;Ward, JM
本章综述了渗透率转换孔结构元素识别的最新进展。环孢菌素A(CsA)抑制毛孔的发现被证明是有益的。不同的方法表明，CsA通过与亲环素(CYP)-D结合来阻断毛孔。特别是，由光活性CsA衍生物原位标记CYP-D的共价标记表明，孔配体对CsA堵塞孔并与CYP-D结合的程度具有相同的影响。认识到CYP-D是一个关键成分，使其他成分得以拆分。使用CYP-D融合蛋白作为亲和基质，发现CYP-D与电压依赖性阴离子通道(外膜)和腺嘌呤核苷酸转位酶(内膜)的1：1复合体结合非常强烈。我们目前的模型设想，在线粒体内膜和外膜之间的接触点，毛孔是这三个组分之间的复合体。这与最近含有这些蛋白质的蛋白质组分的孔活动重组是一致的。这些蛋白质之间相互作用的强度表明，它可能是一种永久性的特征，而不是只有在病理条件下才能组装。钙，毛孔的关键激活剂，似乎并不影响毛孔的组装；相反，表明了一种变构作用，允许毛孔闪烁进入开放状态。CsA抑制毛孔闪烁，降低与钙的结合亲和力。腺嘌呤核苷酸转位酶或电压依赖的阴离子通道(通过内膜插入)是否提供内膜孔尚未得到解决，与此问题相关的数据也被记录在案。
This chapter reviews recent advances in the identification of the structural elements of the permeability transition pore. The discovery that cyclosporin A (CsA) inhibits the pore proved instrumental. Various approaches indicate that CsA blocks the pore by binding to cyclophilin (CyP)-D. In particular, covalent labelling of CyP-D in situ by a photoactive CsA derivative has shown that pore ligands have the same effects on the degree to which CsA both blocks the pore and binds to CyP-D. The recognition that CyP-D is a key component has enabled the other constituents to be resolved. Use of a CyP-D fusion protein as affinity matrix has revealed that CyP-D binds very strongly to 1:1 complexes of the voltage-dependent anion channel (from the outer membrane) and adenine nucleotide translocase (inner membrane). Our current model envisages that the pore arises as a complex between these three components at contact sites between the mitochondrial inner and outer membranes. This is in line with recent reconstitutions of pore activity from protein fractions containing these proteins. The strength of interaction between these proteins suggests that it may be a permanent feature rather than assembled only under pathological conditions. Calcium, the key activator of the pore, does not appear to affect pore assembly; rather, an allosteric action allowing pore flicker into an open state is indicated. CsA inhibits pore flicker and lowers the binding affinity for calcium. Whether adenine nucleotide translocase or the voltage-dependent anion channel (via inner membrane insertion) provides the inner membrane pore has not been settled, and data relevant to this issue are also documented.