cryo-EM分辨率革命预示了我们对具有快速增加的高分辨率结构的真核脂质翻转酶的理解的新时代。Flippase属于ATPase(IV型P型ATPase)的P4家族,在很大程度上遵循了针对更广泛研究的阳离子转运P型ATPase提出的反应循环。然而,与规范的P型ATP酶不同,在磷酸化半反应中没有翻转酶货物被运输。而不是被释放到细胞内或细胞外环境中,脂质货物在膜的内部小叶处被运输到目的地。最近的翻转酶结构揭示了脂质运输周期中的多个构象状态。尽管如此,捕获“运输中”脂质货物的关键构象状态仍然缺失。在这次审查中,我们强调了这些脂质转运蛋白的惊人结构进步,讨论文献中关于催化和调节机制的各种观点,并阐明了进一步破译脂质翻转的详细分子机制的未来方向。
The cryo-EM resolution revolution has heralded a new era in our understanding of eukaryotic lipid flippases with a rapidly growing number of high-resolution structures. Flippases belong to the P4 family of ATPases (type IV P-type ATPases) that largely follow the reaction cycle proposed for the more extensively studied cation-transporting P-type ATPases. However, unlike the canonical P-type ATPases, no flippase cargos are transported in the phosphorylation half-reaction. Instead of being released into the intracellular or extracellular milieu, lipid cargos are transported to their destination at the inner leaflet of the membrane. Recent flippase structures have revealed multiple conformational states during the lipid transport cycle. Nonetheless, critical conformational states capturing the lipid cargo \"in transit\" are still missing. In this review, we highlight the amazing structural advances of these lipid transporters, discuss various perspectives on catalytic and regulatory mechanisms in the literature, and shed light on future directions in further deciphering the detailed molecular mechanisms of lipid flipping.