Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA.
Department of Biochemistry, Weill Cornell Medical College, New York, NY, USA.
Nat Commun. 2022 May 11;13(1):2604. doi: 10.1038/s41467-022-30300-z.
TMEM16 scramblases dissipate the plasma membrane lipid asymmetry to activate multiple eukaryotic cellular pathways. Scrambling was proposed to occur with lipid headgroups moving between leaflets through a membrane-spanning hydrophilic groove. Direct information on lipid-groove interactions is lacking. We report the 2.3 Å resolution cryogenic electron microscopy structure of the nanodisc-reconstituted Ca-bound afTMEM16 scramblase showing how rearrangement of individual lipids at the open pathway results in pronounced membrane thinning. Only the groove's intracellular vestibule contacts lipids, and mutagenesis suggests scrambling does not require specific protein-lipid interactions with the extracellular vestibule. We find scrambling can occur outside a closed groove in thinner membranes and is inhibited in thicker membranes, despite an open pathway. Our results show afTMEM16 thins the membrane to enable scrambling and that an open hydrophilic pathway is not a structural requirement to allow rapid transbilayer movement of lipids. This mechanism could be extended to other scramblases lacking a hydrophilic groove.
TMEM16 scramblases 瓦解质膜脂质的不对称性，以激活多种真核细胞途径。据推测，scrambling 是通过跨膜亲水头基在小叶之间穿过一个亲水通道来发生的。目前缺乏关于脂质通道相互作用的直接信息。我们报告了纳米盘重建的 Ca 结合 afTMEM16 scramblase 的 2.3Å 分辨率低温电子显微镜结构，该结构显示了开放途径中单个脂质的重新排列如何导致明显的膜变薄。只有通道的细胞内前庭与脂质接触，并且突变分析表明 scramblase 不需要与细胞外前庭的特定蛋白-脂质相互作用。我们发现，在较薄的膜中，scrambling 可以在封闭通道之外发生，并且尽管存在开放途径，但在较厚的膜中会受到抑制。我们的结果表明，afTMEM16 使膜变薄以实现 scrambling，并且开放的亲水途径不是允许脂质快速跨膜运动的结构要求。这种机制可以扩展到其他缺乏亲水通道的 scramblases。
