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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn~(2+) efflux and protects against toxicity
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Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn~(2+) efflux and protects against toxicity

机译：高尔基体P型ATPase中功能增强突变的鉴定，该突变增强Mn〜（2+）外排并防止毒性

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摘要

P-type ATPases transport a wide array of ions, regulate diverse cellular processes, and are implicated in a number of human diseases. However, mechanisms that increase ion transport by these ubiquitous proteins are not known. SPCA1 is a P-type pump that transports Mn~(2+) from the cytosol into the Golgi. We developed an intra-Golgi Mn~(2+) sensor and used it to screen for mutations introduced in SPCA1, on the basis of its predicted structure, which could increase its Mn~(2+) pumping activity. Remarkably, a point mutation (Q747A) predicted to increase the size of its ion permeation cavity enhanced the sensor response and a compensatory mutation restoring the cavity to its original size abolished this effect. In vivo and in vitro Mn~(2+) transport assays confirmed the hyper-activity of SPCA1-Q747A. Furthermore, increasing Golgi Mn~(2+) transport by expression of SPCA1-Q747A increased cell viability upon Mn~(2+) exposure, supporting the therapeutic potential of increased Mn~(2+) uptake by the Golgi in the management of Mn~(2+)-induced neurotoxicity.
机译：P型ATP酶运输各种各样的离子，调节多种细胞过程，并牵涉到许多人类疾病中。但是，增加这些普遍存在的蛋白质增加离子转运的机制尚不清楚。 SPCA1是一种P型泵，可将Mn〜（2+）从胞质溶胶中转运到高尔基体中。我们开发了一种高尔基体内Mn〜（2+）传感器，并根据其预测的结构将其用于筛选SPCA1中引入的突变，这可以增加其Mn〜（2+）的泵浦活性。值得注意的是，点突变（Q747A）预计会增加其离子渗透腔的大小，从而增强了传感器的响应，而补偿突变将腔恢复到其原始大小，则消除了这种影响。体内和体外Mn〜（2+）转运试验证实了SPCA1-Q747A的过度活跃。此外，通过SPCA1-Q747A的表达增加高尔基体的Mn〜（2+）转运可增加Mn〜（2+）暴露时的细胞活力，从而支持高尔基体在锰管理中增加Mn〜（2+）的治疗潜力。 〜（2+）诱导的神经毒性。

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