日本东京大学Osamu Nureki、Tomohiro Nishizawa等研究人员合作解析了IV型P型三磷酸腺苷酶（P4-ATP酶）翻转酶的冷冻电镜结构，相关论文发表在2019年9月13日出版的《科学》杂志上。

研究人员报道了人类ATP8A1-CDC50a 异源复合物的六种不同中间体冷冻电镜结构，分辨率为2.6至3.3埃，从而阐明了这种P4-ATP酶的脂质转运循环。ATP依赖性磷酸化引发磷酸化结构域中的磷酸化位点周围的调节器结构域出现大的旋转运动，并伴随第一和第二跨膜螺旋的横向移位，从而允许磷脂酰丝氨酸结合。磷脂头部基团穿过亲水性裂缝，而酰基链暴露于脂质环境。这些发现促进了人们对翻转酶机制以及P4-ATP酶疾病相关突变的理解。

据介绍，在真核细胞膜中，IV型P型三磷酸腺苷酶（P4-ATP酶）介导磷脂从外部到内部的转移并维持脂质不对称性，这对于膜运输和信号传导途径是至关重要的。

附：英文原文

Title:Cryo-EM structures capture the transport cycle of the P4-ATPase flippase

Author:Masahiro Hiraizumi1,2, Keitaro Yamashita1,3, Tomohiro Nishizawa1,*, Osamu Nureki1,*

Issue&Volume: Vol 365, Issue 6458

Abstract:

In eukaryotic membranes, type IV P-type adenosine triphosphatases (P4-ATPases) mediate the translocation of phospholipids from the outer to the inner leaflet and maintain lipid asymmetry, which is critical for membrane trafficking and signaling pathways. Here, we report the cryo–electron microscopy structures of six distinct intermediates of the human ATP8A1-CDC50a heterocomplex at resolutions of 2.6 to 3.3 angstroms, elucidating the lipid translocation cycle of this P4-ATPase. ATP-dependent phosphorylation induces a large rotational movement of the actuator domain around the phosphorylation site in the phosphorylation domain, accompanied by lateral shifts of the first and second transmembrane helices, thereby allowing phosphatidylserine binding. The phospholipid head group passes through the hydrophilic cleft, while the acyl chain is exposed toward the lipid environment. These findings advance our understanding of the flippase mechanism and the disease-associated mutants of P4-ATPases.

DOI: 10.1126/science.aay3353

Source:https://science.sciencemag.org/content/365/6458/1149