Department of Immunology, Kanazawa Medical University, Uchinada, Japan.
Graduate School of Science and Engineering, Ibaraki University, Japan.
FEBS Lett. 2018 Aug;592(15):2647-2657. doi: 10.1002/1873-3468.13181. Epub 2018 Jul 16.
Sortilin is a multifunctional sorting receptor involved in cytokine production in immune cells. To understand the mechanism of Sortilin-mediated cytokine trafficking, we determined the 2.45-Å structure of the dimerized Sortilin ectodomain (sSortilin or the Vps10-domain) crystallized at acidic pH. Substantial conformational changes upon dimerization lead to the intermolecular hydrophobic interaction between the conserved E455 and F137. Analysis of the electrostatic surface and size-exclusion chromatography revealed that sSortilin dimerization occurs due to an increase in hydrophobic interactions at the neutral dimer interface at acidic pH. The N682-attached N-glycan in the vicinity of the dimer interface implies its involvement in the dimerization. The disruption of Sortilin dimerization by mutations impairs efficient interferon-alpha secretion from cells. These results suggest the functional importance of Sortilin dimerization in cytokine trafficking.
Sortilin 是一种多功能分拣受体，参与免疫细胞中的细胞因子产生。为了了解 Sortilin 介导的细胞因子运输的机制，我们在酸性 pH 值下确定了二聚化的 Sortilin 外域（sSortilin 或 Vps10 结构域）的 2.45-Å 结构。二聚化引起的构象变化导致保守的 E455 和 F137 之间的分子间疏水相互作用。静电表面分析和尺寸排阻色谱表明，sSortilin 二聚化是由于酸性 pH 值下中性二聚体界面上疏水相互作用的增加所致。二聚体界面附近附着在 N682 上的 N-聚糖暗示其参与二聚化。突变破坏 Sortilin 二聚化会损害细胞中干扰素-α的有效分泌。这些结果表明细胞因子运输中 Sortilin 二聚化的功能重要性。
