Molecular Discrimination between Two Conformations of Sphingomyelin in Plasma Membranes
Molecular Discrimination between Two Conformations of Sphingomyelin in Plasma Membranes
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DOI：
10.1016/j.cell.2018.12.042
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发表时间：
2019-02-21
期刊：
影响因子：
64.5
通讯作者：
Radhakrishnan, Arun
中科院分区：
文献类型：
--
作者：
Endapally, Shreya;Frias, Donna;Radhakrishnan, Arun
鞘磷脂和胆固醇是动物细胞质膜中富含的必需脂质，它们在质膜中相互作用，调节膜特性和许多细胞内信号传导过程。尽管进行了大量的研究，但这些脂质在膜中的相互作用还没有得到很好的理解。在这里，对溶脂素A （OlyA）的结构和生化分析表明，当膜同时含有鞘磷脂和胆固醇时，鞘磷脂在膜中采用两种不同的构象。一种由OlyA结合的构象是由与胆固醇的化学计量学、放热相互作用诱导的，其性质与鞘磷脂/胆固醇复合物一致。在第二种构象中，鞘磷脂不含胆固醇，也不与OlyA结合。点突变消除了OlyA区分这两种构象的能力。在细胞中，鞘磷脂/胆固醇复合物的水平在质膜胆固醇浓度范围内保持恒定，从而能够精确调节胆固醇的化学活性。
Sphingomyelin and cholesterol are essential lipids that are enriched in plasma membranes of animal cells, where they interact to regulate membrane properties and many intracellular signaling processes. Despite intense study, the interaction between these lipids in membranes is not well understood. Here, structural and biochemical analyses of ostreolysin A (OlyA), a protein that binds to membranes only when they contain both sphingomyelin and cholesterol, reveal that sphingomyelin adopts two distinct conformations in membranes when cholesterol is present. One conformation, bound by OlyA, is induced by stoichiometric, exothermic interactions with cholesterol, properties that are consistent with sphingomyelin/cholesterol complexes. In its second conformation, sphingomyelin is free from cholesterol and does not bind OlyA. A point mutation abolishes OlyA's ability to discriminate between these two conformations. In cells, levels of sphingomyelin/cholesterol complexes are held constant over a wide range of plasma membrane cholesterol concentrations, enabling precise regulation of the chemical activity of cholesterol.