Coiled-coil binding of the leucine zipper domains of APOL1 is necessary for the open cation channel conformation.
Coiled-coil binding of the leucine zipper domains of APOL1 is necessary for the open cation channel conformation.
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DOI：
10.1016/j.jbc.2021.101009
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Thomson R
中科院分区：
文献类型：
--
作者：
Schaub C;Lee P;Racho-Jansen A;Giovinazzo J;Terra N;Raper J;Thomson R
载脂蛋白L-I（APOL 1）是先天免疫的通道形成效应物。常见的人类APOL 1变体G 0提供针对某些锥虫属和利什曼原虫属寄生虫物种的感染的保护，但它不能针对负责人类非洲锥虫病的锥虫提供保护。人类APOL 1变体G1和G2可以保护人类感染性锥虫，但也会增加患慢性肾脏疾病的风险。锥虫杀伤活性取决于APOL 1在酸性pH下插入膜并形成pH门控阳离子通道的能力。我们先前将通道的孔衬区域映射到C-末端结构域（残基332-398），并鉴定了促进酸性pH依赖性膜插入的膜插入结构域（MID，残基177-228）。在这篇文章中，我们进一步研究了阳离子通道形成的APOL 1的结构决定因素。使用定点诱变和有针对性的化学修饰的组合，我们的数据表明，C-末端七重复序列（残基368-395）是一个真正的亮氨酸拉链结构域（ZIP），需要阳离子通道的形成以及锥虫和哺乳动物细胞的裂解。使用全蛋白半胱氨酸扫描诱变，加上取代的半胱氨酸可及性方法，我们确定，在开放通道状态下，N-末端结构域和C-末端ZIP结构域都暴露在膜的腔内/细胞外侧，并提供证据表明，每个APOL 1单体有助于四个跨膜结构域的开放阳离子通道构象。基于这些数据，我们提出了一个寡聚拓扑模型，其中开放的APOL 1阳离子通道是从C-末端ZIP结构域的卷曲螺旋协会组装。
Apolipoprotein L-I (APOL1) is a channel-forming effector of innate immunity. The common human APOL1 variant G0 provides protection against infection with certain Trypanosoma and Leishmania parasite species, but it cannot protect against the trypanosomes responsible for human African trypanosomiasis. Human APOL1 variants G1 and G2 protect against human-infective trypanosomes but also confer a higher risk of developing chronic kidney disease. Trypanosome-killing activity is dependent on the ability of APOL1 to insert into membranes at acidic pH and form pH-gated cation channels. We previously mapped the channel’s pore-lining region to the C-terminal domain (residues 332–398) and identified a membrane-insertion domain (MID, residues 177–228) that facilitates acidic pH-dependent membrane insertion. In this article, we further investigate structural determinants of cation channel formation by APOL1. Using a combination of site-directed mutagenesis and targeted chemical modification, our data indicate that the C-terminal heptad-repeat sequence (residues 368–395) is a bona fide leucine zipper domain (ZIP) that is required for cation channel formation as well as lysis of trypanosomes and mammalian cells. Using protein-wide cysteine-scanning mutagenesis, coupled with the substituted cysteine accessibility method, we determined that, in the open channel state, both the N-terminal domain and the C-terminal ZIP domain are exposed on the intralumenal/extracellular side of the membrane and provide evidence that each APOL1 monomer contributes four transmembrane domains to the open cation channel conformation. Based on these data, we propose an oligomeric topology model in which the open APOL1 cation channel is assembled from the coiled-coil association of C-terminal ZIP domains.
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DOI：
10.1126/science.1193032
发表时间：
2010-08-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Genovese G;Friedman DJ;Ross MD;Lecordier L;Uzureau P;Freedman BI;Bowden DW;Langefeld CD;Oleksyk TK;Uscinski Knob AL;Bernhardy AJ;Hicks PJ;Nelson GW;Vanhollebeke B;Winkler CA;Kopp JB;Pays E;Pollak MR
通讯作者：
Pollak MR
先天免疫途径调节肾病基因载脂蛋白L1。
影响因子：
19.6
作者：
通讯作者：
--
DOI：
10.1084/jem.20071463
发表时间：
2008-08-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Molina-Portela MP;Samanovic M;Raper J
通讯作者：
Raper J
影响因子：
8
作者：
HU, JC;NEWELL, NE;SAUER, RT
通讯作者：
SAUER, RT
影响因子：
19.6
作者：
Lannon, Herbert;Shah, Shrijal S.;Friedman, David J.
通讯作者：
Friedman, David J.