Kidney-disease-associated variants of Apolipoprotein L1 show gain of function in cation channel activity.
Kidney-disease-associated variants of Apolipoprotein L1 show gain of function in cation channel activity.
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DOI：
10.1074/jbc.ra120.013943
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Edwards JC
中科院分区：
文献类型：
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作者：
Bruno J;Edwards JC
已知载脂蛋白L1(APOL1)的变异导致非洲血统的人患某些进行性肾病的风险增加。APOL1是一种两性性蛋白质，可以插入磷脂膜，并根据pH的不同对磷脂膜赋予阴离子或阳离子选择性通透性。这些活动是否在不同的变异体中有所不同，或者它们是否与疾病的发病机制有关，目前尚不清楚。我们使用电压驱动的磷脂小泡离子通量和稳定的膜结合分析来评估APOL1亚型之间的差异。与参考蛋白相比，这两个与肾脏疾病相关的变异体的阳离子选择性离子渗透酶活性显著增加(约两倍)。相反，我们发现在低pH条件下，不同亚型的阴离子选择性渗透酶活性没有差异。与参考序列相比，在支持阳离子通透酶活性的条件下，这两个与疾病相关的变异体与磷脂囊泡显示出更稳定的结合，这表明活性的增加可能是由于更有效的膜结合和插入。在阴离子渗透酶活性的最佳条件下，不同亚型之间的膜结合没有差异。这些数据支持一种模型，在该模型中，阳离子渗透性增强可能导致与高危APOL1等位基因相关的进行性肾脏疾病。
Variants in Apolipoprotein L1 (ApoL1) are known to be responsible for increased risk of some progressive kidney diseases among people of African ancestry. ApoL1 is an amphitropic protein that can insert into phospholipid membranes and confer anion- or cation-selective permeability to phospholipid membranes depending on pH. Whether these activities differ among the variants or whether they contribute to disease pathogenesis is unknown. We used assays of voltage-driven ion flux from phospholipid vesicles and of stable membrane association to assess differences among ApoL1 isoforms. There is a significant (approximately twofold) increase in the cation-selective ion permease activity of the two kidney-disease-associated variants compared with the reference protein. In contrast, we find no difference in the anion-selective permease activity at low pH among the isoforms. Compared with the reference sequence, the two disease-associated variants show increased stable association with phospholipid vesicles under conditions that support the cation permease activity, suggesting that the increased activity may be due to more efficient membrane association and insertion. There is no difference in membrane association among isoforms under optimal conditions for the anion permease activity. These data support a model in which enhanced cation permeability may contribute to the progressive kidney diseases associated with high-risk ApoL1 alleles.