Enthalpy-driven interactions with sulfated glycosaminoglycans promote cell membrane penetration of arginine peptides.
Enthalpy-driven interactions with sulfated glycosaminoglycans promote cell membrane penetration of arginine peptides.
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焓驱动的与硫酸化糖胺聚糖的相互作用促进精氨酸肽的细胞膜渗透。
DOI：
10.1016/j.bbamem.2016.03.021
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Saito H
中科院分区：
文献类型：
--
作者：
Takechi-Haraya Y;Nadai R;Kimura H;Nishitsuji K;Uchimura K;Sakai-Kato K;Ka-wakami K;Shigenaga A;Kawakami T;Otaka A;Hojo H;Sakashita N;Saito H
精氨酸肽渗透细胞膜的第一步被认为是通过细胞表面精氨酸残基的正电荷和硫酸化糖胺聚糖 (GAG) 的负电荷之间的静电相互作用发生的。然而，精氨酸肽与 GAG 的分子相互作用仍不清楚。在这里，我们比较了 Tat、R8 和 Rev 及其类似物的几种精氨酸肽与肝素的相互作用与细胞膜穿透效率的关系。精氨酸肽与肝素的高亲和力结合被证明是由大的有利的焓贡献驱动的，可能反映了精氨酸残基与肝素的硫酸基团的多齿氢键。有趣的是，所有精氨酸残基均被赖氨酸残基取代的赖氨酸肽尽管与肝素具有相当大的结合，但表现出可忽略不计的结合焓。在CHO-K1细胞中，精氨酸肽表现出很强的细胞穿透能力，而其相应的赖氨酸肽则不能穿透细胞。氯酸盐处理细胞可防止 GAG 链硫酸化，从而显着降低精氨酸肽的细胞渗透程度。值得注意的是，发现精氨酸肽的细胞渗透效率与与肝素的有利结合焓相关。这些结果表明，与硫酸化 GAG（例如硫酸乙酰肝素）的焓驱动的强相互作用在精氨酸肽的有效细胞膜渗透中发挥着关键作用。
The first step of cell membrane penetration of arginine peptides is thought to occur via electrostatic interactions between positive charges of arginine residues and negative charges of sulfated glycosaminoglycans (GAGs) on the cell surface. However, the molecular interaction of arginine peptides with GAG still remains unclear. Here, we compared the interactions of several arginine peptides of Tat, R8, and Rev and their analogues with heparin in relation to the cell membrane penetration efficiency. The high-affinity binding of arginine peptides to heparin was shown to be driven by large favorable enthalpy contributions, possibly reflecting multidentate hydrogen bondings of arginine residues with sulfate groups of heparin. Interestingly, the lysine peptides in which all arginine residues are substituted with lysine residues exhibited negligible binding enthalpy despite of their considerable binding to heparin. In CHO-K1 cells, arginine peptides exhibited a great cell-penetrating ability whereas their corresponding lysine peptides did not penetrate into cells. The degree of cell penetration of arginine peptides markedly decreased by the chlorate treatment of cells which prevents the sulfation of GAG chains. Significantly, the cell penetration efficiency of arginine peptides was found to be correlated with the favorable enthalpy of binding to heparin. These results suggest that the enthalpy-driven strong interaction with sulfated GAGs such as heparan sulfate plays a critical role in the efficient cell membrane penetration of arginine peptides.