Transport Cycle of Plasma Membrane Flippase ATP11C by Cryo-EM
Transport Cycle of Plasma Membrane Flippase ATP11C by Cryo-EM
复制标题
DOI：
10.1016/j.celrep.2020.108208
复制
发表时间：
2020-09-29
期刊：
影响因子：
8.8
通讯作者：
Abe, Kazuhiro
中科院分区：
文献类型：
--
作者：
Nakanishi, Hanayo;Nishizawa, Tomohiro;Abe, Kazuhiro
ATP11C是一种质膜磷脂翻转酶，它维持了小叶内积累的磷脂酰丝氨酸的不对称分布。依赖于caspase的ATP11C失活对于“吃我”的凋亡信号，磷脂酰丝氨酸暴露是必不可少的，它促使吞噬细胞吞噬细胞。我们展示了ATP11C在3.0-4.0埃分辨率的五种不同输运循环状态下的六种低温EM结构。结构比较揭示了磷酸化驱动的结构域移动与磷脂结合。磷脂结合态的三种结构显示了伴随着跨膜螺旋的重排和闭塞部位的未缠绕部分的磷脂移位，从而详细说明了头基识别的基础和跨膜沟中蛋白质结合的酰基链的位置。不变的Lys880和周围的氢键网络是螺旋弯曲和精确的P结构域倾斜的支点，这是去磷酸化的关键。这些结构详细说明了ATP11C磷脂转运的关键特征，并出现了一种共同的基本机制。
ATP11C, a plasma membrane phospholipid flippase, maintains the asymmetric distribution of phosphatidylserine accumulated in the inner leaflet. Caspase-dependent inactivation of ATP11C is essential for an apoptotic "eat me'' signal, phosphatidylserine exposure, which prompts phagocytes to engulf cells. We show six cryo-EM structures of ATP11C at 3.0-4.0 angstrom resolution in five different states of the transport cycle. A structural comparison reveals phosphorylation-driven domain movements coupled with phospholipid binding. Three structures of phospholipid-bound states visualize phospholipid translocation accompanied by the rearrangement of transmembrane helices and an unwound portion at the occlusion site, and thus they detail the basis for head group recognition and the locality of the protein-bound acyl chains in transmembrane grooves. Invariant Lys880 and the surrounding hydrogen-bond network serve as a pivot point for helix bending and precise P domain inclination, which is crucial for dephosphorylation. The structures detail key features of phospholipid translocation by ATP11C, and a common basic mechanism for flippases is emerging.