A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes
A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes
复制标题
DOI：
10.1172/jci148005
复制
发表时间：
2021-09-15
影响因子：
15.9
通讯作者：
Nagata, Shigekazu
中科院分区：
文献类型：
--
作者：
Segawa, Katsumori;Kikuchi, Atsuo;Nagata, Shigekazu
ATP 11 A将磷脂酰丝氨酸（PtdSer）而不是磷脂酰胆碱（PtdCho）从质膜的外叶转位到内叶，从而维持PtdSer的不对称分布。在这里，我们检测到一个从头杂合点突变的ATP 11 A的患者发育迟缓和神经功能恶化。携带相应突变的小鼠在围产期死于神经系统疾病。该突变导致ATP 11 A第一跨膜段的氨基酸替换（Q84 E），突变的ATP 11 A翻转PtdCho。分子动力学模拟表明，突变允许PtdCho结合在基板进入网站。异常PtdCho翻转显着降低了质膜外叶中PtdCho的浓度，而外叶中的鞘磷脂（SM）浓度增加。磷脂分布的这种变化改变了细胞特性，包括细胞生长、胆固醇稳态和对鞘磷脂酶的敏感性。基质辅助激光解吸电离成像质谱（MALDI-IMS）显示，在Q84 E基因敲入小鼠胚胎的大脑中SM水平显着增加。这些结果提供了深入了解质膜翻转酶的底物特异性的生理重要性的PtdCho和SM的适当分布。
ATP11A translocates phosphatidylserine (PtdSer), but not phosphatidylcholine (PtdCho), from the outer to the inner leaflet of plasma membranes, thereby maintaining the asymmetric distribution of PtdSer. Here, we detected a de novo heterozygous point mutation of ATP11A in a patient with developmental delays and neurological deterioration. Mice carrying the corresponding mutation died perinatally of neurological disorders. This mutation caused an amino acid substitution (Q84E) in the first transmembrane segment of ATP11A, and mutant ATP11A flipped PtdCho. Molecular dynamics simulations revealed that the mutation allowed PtdCho binding at the substrate entry site. Aberrant PtdCho flipping markedly decreased the concentration of PtdCho in the outer leaflet of plasma membranes, whereas sphingomyelin (SM) concentrations in the outer leaflet increased. This change in the distribution of phospholipids altered cell characteristics, including cell growth, cholesterol homeostasis, and sensitivity to sphingomyelinase. Matrix-assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) showed a marked increase of SM levels in the brains of Q84E-knockin mouse embryos. These results provide insights into the physiological importance of the substrate specificity of plasma membrane flippases for the proper distribution of PtdCho and SM.