离子传输Na+的功能,K+-ATP酶依赖于生物膜中周围的脂质环境。已观察到跨膜结构域内的两个已建立的脂质相互作用位点A和B诱导蛋白质活化和稳定。分别。此外,脂质介导的抑制作用已被分配到C位点,但确切的位置没有实验证实。此外,居住在膜蛋白界面中的疾病突变体对脂质相互作用的可能影响仍然相对未表征。我们模拟了人类Na+,K+-ATP酶α1β1FXYD在E1和E2状态下的同源性模型,多组分质膜,以确定野生型和疾病突变体脂质-蛋白质相互作用。在所建立的位点A和B处的模拟野生型脂质相互作用与实验结果一致,从而证实了膜蛋白模型系统。特征越少,提议的抑制位点C由缺乏抑制特性的脂质主导。相反,在细胞外侧确定了两个抑制脂质的位点,还有一个细胞质CHL结合位点,提供了Na的推定替代位置,K+-ATP酶抑制。三种疾病突变,Leu302Arg,Glu840Arg和Met859Arg位于脂质-蛋白质界面,并引起脂质相互作用的急剧变化。模拟结果表明,脂质与人Na+的相互作用,质膜中的K+-ATPaseα1β1FXYD蛋白具有高度的状态依赖性,可被位于脂质界面的疾病突变所干扰,这可以为了解遗传疾病开辟新的场所。
The function of ion-transporting Na+,K+-ATPases depends on the surrounding lipid environment in biological membranes. Two established lipid-interaction sites A and B within the transmembrane domain have been observed to induce protein activation and stabilization, respectively. In addition, lipid-mediated inhibition has been assigned to a site C, but with the exact location not experimentally confirmed. Also, possible effects on lipid interactions by disease mutants dwelling in the membrane-protein interface remain relatively uncharacterized. We simulated human Na+,K+-ATPase α1β1FXYD homology models in E1 and E2 states in an asymmetric, multicomponent plasma membrane to determine both wild-type and disease mutant lipid-protein interactions. The simulated wild-type lipid interactions at the established sites A and B were in agreement with experimental results thereby confirming the membrane-protein model system. The less well-characterized, proposed inhibitory site C was dominated by lipids lacking inhibitory properties. Instead, two sites hosting inhibitory lipids were identified at the extracellular side and also a cytoplasmic CHL-binding site that provide putative alternative locations of Na+,K+-ATPase inhibition. Three disease mutations, Leu302Arg, Glu840Arg and Met859Arg resided in the lipid-protein interface and caused drastic changes in the lipid interactions. The simulation results show that lipid interactions to the human Na+,K+-ATPase α1β1FXYD protein in the plasma membrane are highly state-dependent and can be disturbed by disease mutations located in the lipid interface, which can open up for new venues to understand genetic disorders.