University of Bern, Department of Chemistry and Biochemistry, Bern, Switzerland.
University of Kiel, Institute of Human Nutrition and Food Science, Kiel, Germany.
Sci Rep. 2017 Jul 10;7(1):4970. doi: 10.1038/s41598-017-05148-9.
Vitamin E is one of the most important natural antioxidants, protecting polyunsaturated fatty acids in the membranes of cells. Among different chemical isoforms assimilated from dietary regimes, RRR-α-tocopherol is the only one retained in higher animals. This is possible thanks to α-Tocopherol Transfer Protein (α-TTP), which extracts α-tocopherol from endosomal compartments in liver cells, facilitating its distribution into the body. Here we show that, upon binding to its substrate, α-TTP acquires tendency to aggregation into thermodynamically stable high molecular weight oligomers. Determination of the structure of such aggregates by X-ray crystallography revealed a spheroidal particle formed by 24 protein monomers. Oligomerization is triggered by refolding of the N-terminus. Experiments with cultured cell monolayers demonstrate that the same oligomers are efficiently transported through an endothelial barrier (HUVEC) and not through an epithelial one (Caco-2). Discovery of a human endogenous transport protein with intrinsic capability of crossing endothelial tissues opens to new ways of drug delivery into the brain or other tissues protected by endothelial barriers.
维生素 E 是最重要的天然抗氧化剂之一，能够保护细胞膜中多不饱和脂肪酸。在从饮食中摄取的不同化学异构形式中，RRR-α-生育酚是唯一一种在高等动物体内被保留的物质。这要归功于α-生育酚转移蛋白（α-TTP），它能从肝细胞的内体隔室中提取α-生育酚，促进其在体内的分布。在这里，我们发现，在与底物结合后，α-TTP 会倾向于聚集形成热力学稳定的高分子量寡聚物。通过 X 射线晶体学确定此类聚集体的结构，揭示了由 24 个蛋白质单体形成的球形颗粒。寡聚化是由 N 端的重折叠触发的。在培养的细胞单层上进行的实验表明，相同的寡聚物可以有效地穿过内皮屏障（HUVEC），而不能穿过上皮细胞（Caco-2）。发现具有内在穿过内皮组织能力的人类内源性转运蛋白，为药物递送到由内皮屏障保护的大脑或其他组织开辟了新途径。
