Cryo-EM structures capture the transport cycle of the P4-ATPase flippase
Cryo-EM structures capture the transport cycle of the P4-ATPase flippase
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DOI：
10.1126/science.aay3353
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发表时间：
2019-09-13
期刊：
影响因子：
56.9
通讯作者：
Nureki, Osamu
中科院分区：
文献类型：
--
作者：
Hiraizumi, Masahiro;Yamashita, Keitaro;Nureki, Osamu
在真核细胞膜中，IV型P-型腺苷三磷酸酶（P4-ATP酶）介导磷脂从外叶到内叶的移位并维持脂质不对称性，这对于膜运输和信号传导途径至关重要。这里.我们报告了六种不同的人ATP 8A 1-CDC 50 a杂合物中间体的冷冻电子显微镜结构，分辨率为2.6 - 33埃，阐明了这种P4-ATP酶的脂质易位循环。ATP依赖性磷酸化诱导了磷酸化结构域中的磷酸化位点周围的致动器结构域的大的旋转运动，伴随着第一和第二跨膜螺旋的侧向移位，从而允许磷脂酰丝氨酸结合。磷脂头基通过亲水裂缝，而酰基链暴露于脂质环境。这些发现推进了我们对翻转酶机制和P4-ATP酶的疾病相关突变体的理解。
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 33 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.