Crystal structure of the ligand‐free form of the Vps10 ectodomain of dimerized Sortilin at acidic pH

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.