Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Sortilin

Sortilin is a neuronal receptor involved in transmembrane signaling, endocytosis, and intracellular sorting of proteins. It cycles through a number of cellular compartments where it encounters various acidic conditions. The crystal structure of the sortilin ectodomain has previously been determined at neutral pH. Here, we present the 3.5-Å resolution crystal structure of sortilin at pH 5.5, which represents an environment similar to that of late endosomes, where ligands are released. The structure reveals an overall distortion of the 10-bladed β-propeller domain. This distortion and specific conformational changes, caused by protonation of a number of histidine residues, render the currently known binding sites unavailable for ligand binding. Access to the binding sites is furthermore blocked by a reversible and pH-dependent formation of tight sortilin dimers, also confirmed by electron microscopy, size-exclusion chromatography, and mutational studies. This study reveals how sortilin binding sites are disrupted and explains pH-dependent ligand affinity. [Display omitted] •Sortilin ectodomain forms dimers at low pH•The 10-bladed β-propeller domain is elliptical at low pH•Binding sites of sortilin are disordered and inaccessible at low pH•Dimerization of sortilin is pH-reversible Januliene et al. shows that low pH induces sortilin to form tight, pH-reversible dimers and undergo conformational changes, which distort the two ligand binding sites. This leads to the loss of ligand affinity, thereby enabling ligand release and deposit of the cargo in specific cellular compartments.