Nephrotic-syndrome-associated mutation of KANK2 induces pathologic binding competition with physiological interactor KIF21A.
Nephrotic-syndrome-associated mutation of KANK2 induces pathologic binding competition with physiological interactor KIF21A.
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肾病综合征相关的 KANK2 突变诱导与生理相互作用因子 KIF21A 的病理性结合竞争
DOI：
10.1016/j.jbc.2021.100958
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Yu C
中科院分区：
文献类型：
--
作者：
Xu Y;Guo C;Pan W;Zhao C;Ding Y;Xie X;Wei Z;Sun Y;Yu C
肾病综合征（NS）是一种常见的由肾小球滤过屏障功能障碍引起的肾脏疾病。在NS患者中鉴定的一些基因突变导致含肾锚蛋白重复序列（KANK）蛋白的氨基酸取代，KANK蛋白是通过与各种分子（包括驱动蛋白马达蛋白KIF 21 A）结合来调节肌动蛋白聚合、微管靶向和细胞粘附的支架蛋白。然而，这些突变导致NS的机制尚不清楚。在这里，我们意外地发现，真核生物翻译起始因子4A 1（eIF 4A 1）与NS相关的KANK 2突变体（S684 F）相互作用，而不是野生型蛋白。生化和结构分析表明，病理性突变诱导的异常结合eIF 4A 1 KANK 2在生理KIF 21 A结合位点。竞争结合试验进一步表明，eIF 4A 1可以与KIF 21 A竞争与KANK 2的S684 F突变体相互作用。在培养的小鼠足细胞中，这种S684 F突变体通过与eIF 4A 1结合来干扰KANK 2/KIF 21 A相互作用，并且未能挽救因KANK 2敲除而减少或形态学改变的粘着斑或细胞粘附。这些结构、生化和细胞结果不仅为S684 F突变引起的足细胞缺陷提供了机制解释，而且还显示了结合获得性突变如何导致功能丧失效应。
Nephrotic syndrome (NS) is a common kidney disorder caused by dysfunction of the glomerular filtration barrier. Some genetic mutations identified in NS patients cause amino acid substitutions of kidney ankyrin repeat-containing (KANK) proteins, which are scaffold proteins that regulate actin polymerization, microtubule targeting, and cell adhesion via binding to various molecules, including the kinesin motor protein KIF21A. However, the mechanisms by which these mutations lead to NS are unclear. Here, we unexpectedly found that the eukaryotic translation initiation factor 4A1 (eIF4A1) interacts with an NS-associated KANK2 mutant (S684F) but not the wild-type protein. Biochemical and structural analyses revealed that the pathological mutation induces abnormal binding of eIF4A1 to KANK2 at the physiological KIF21A-binding site. Competitive binding assays further indicated that eIF4A1 can compete with KIF21A to interact with the S684F mutant of KANK2. In cultured mouse podocytes, this S684F mutant interfered with the KANK2/KIF21A interaction by binding to eIF4A1, and failed to rescue the focal adhesion or cell adhesion that had been reduced or morphologically changed by KANK2 knockout. These structural, biochemical, and cellular results not only provide mechanistic explanations for the podocyte defects caused by the S684F mutation, but also show how a gain-of-binding mutation can lead to a loss-of-function effect.
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影响因子：
5.6
作者：
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发表时间：
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