A C-terminal mutation of ATP1A3 underscores the crucial role of sodium affinity in the pathophysiology of rapid-onset dystonia-parkinsonism
A C-terminal mutation of ATP1A3 underscores the crucial role of sodium affinity in the pathophysiology of rapid-onset dystonia-parkinsonism
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DOI：
10.1093/hmg/ddp170
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发表时间：
2009-07-01
影响因子：
3.5
通讯作者：
Sobrido, Maria-Jesus
中科院分区：
文献类型：
--
作者：
Blanco-Arias, Patricia;Einholm, Anja P.;Sobrido, Maria-Jesus
Na+/K+-ATP酶是在维持神经元存活和功能所必需的电化学梯度方面具有根本重要性的离子泵。编码α 3亚型的ATP 1A 3突变可引起速发型肌张力障碍-帕金森综合征（RDP）。我们报告了一例典型RDP患者的从头ATP 1A 3突变，包括在Na+/K+-ATP酶α 3亚基的C末端插入一个酪氨酸残基，这是首次报道的RDP蛋白C末端突变。表达研究表明，有没有缺陷的生物合成或质膜靶向，虽然细胞表达的突变蛋白表现出下降的生存响应哇巴因的挑战。功能分析表明，在突变体中的Na+亲和力急剧减少，这可以理解的野生型和突变体酶的E1和E2构象的基础上的战略位置的C末端相对于第三Na+结合位点的结构建模。戏剧性的临床表现，连同生化研究结果，提供了在体内和体外的证据，在Na+/K+-ATP酶的功能的α-亚基的C末端的关键作用和Na+亲和力的RDP的病理生理学的关键影响。
The Na+/K+-ATPases are ion pumps of fundamental importance in maintaining the electrochemical gradient essential for neuronal survival and function. Mutations in ATP1A3 encoding the alpha 3 isoform cause rapid-onset dystonia-parkinsonism (RDP). We report a de novo ATP1A3 mutation in a patient with typical RDP, consisting of an in-frame insertion of a tyrosine residue at the very C terminus of the Na+/K+-ATPase alpha 3-subunit-the first reported RDP mutation in the C terminus of the protein. Expression studies revealed that there is no defect in the biogenesis or plasma membrane targeting, although cells expressing the mutant protein showed decreased survival in response to ouabain challenge. Functional analysis demonstrated a drastic reduction in Na+ affinity in the mutant, which can be understood by structural modelling of the E1 and E2 conformations of the wild-type and mutant enzymes on the basis of the strategic location of the C terminus in relation to the third Na+ binding site. The dramatic clinical presentation, together with the biochemical findings, provides both in vivo and in vitro evidence for a crucial role of the C terminus of the alpha-subunit in the function of the Na+/K+-ATPase and a key impact of Na+ affinity in the pathophysiology of RDP.