Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
FASEB J. 2019 Mar;33(3):3087-3096. doi: 10.1096/fj.201801873R. Epub 2018 Dec 3.
P4-ATPases, a subfamily of P-type ATPases, were initially identified as aminophospholipid translocases in eukaryotic membranes. These proteins generate and maintain membrane lipid asymmetry by translocating aminophospholipids (phosphatidylserine and phosphatidylethanolamine) from the exoplasmic/lumenal leaflet to the cytoplasmic leaflet. The human genome encodes 14 P4-ATPases, and the cellular localizations, substrate specificities, and cellular roles of these proteins were recently revealed. Numerous P4-ATPases, including ATP8A1, ATP8A2, ATP11A, ATP11B, and ATP11C, transport phosphatidylserine. By contrast, ATP8B1, ATP8B2, and ATP10A transport phosphatidylcholine but not aminophospholipids, although there is a discrepancy regarding the substrate of ATP8B1 in the literature. Some yeast and plant P4-ATPases can also translocate phosphatidylcholine. At least 2 P4-ATPases (ATP8A2 and ATP8B1) are associated with severe human diseases, and other P4-ATPases are implicated in various pathophysiologic conditions in mouse models. Here, we discuss the cellular functions of phosphatidylcholine flippases and suggest a model for the phenotype of progressive familial intrahepatic cholestasis 1 caused by a defect in ATP8B1.-Shin, H.-W., Takatsu, H. Substrates of P4-ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine).
P4-ATPases 是 P 型 ATP 酶亚家族的一种，最初在真核细胞膜中被鉴定为氨基磷脂转运体。这些蛋白质通过将氨基磷脂（磷脂酰丝氨酸和磷脂酰乙醇胺）从外质/腔侧叶转移到细胞质侧叶，从而产生并维持膜脂质的不对称性。人类基因组编码了 14 种 P4-ATPases，这些蛋白质的细胞定位、底物特异性和细胞功能最近才被揭示。许多 P4-ATPases，包括 ATP8A1、ATP8A2、ATP11A、ATP11B 和 ATP11C，都可以转运磷脂酰丝氨酸。相比之下，ATP8B1、ATP8B2 和 ATP10A 则转运磷脂酰胆碱而不是氨基磷脂，尽管文献中关于 ATP8B1 的底物存在差异。一些酵母和植物 P4-ATPases 也可以转运磷脂酰胆碱。至少有 2 种 P4-ATPases（ATP8A2 和 ATP8B1）与严重的人类疾病有关，而其他 P4-ATPases与小鼠模型中的各种病理生理状况有关。在这里，我们讨论了磷脂酰胆碱翻转酶的细胞功能，并提出了 ATP8B1 缺陷引起的进行性家族性肝内胆汁淤积症 1 表型的模型。-Shin, H.-W., Takatsu, H. P4-ATPases 的底物：超越氨基磷脂（磷脂酰丝氨酸和磷脂酰乙醇胺）。
