AI Article Synopsis
- Sortilin is a neuronal receptor that plays a key role in signaling, protein sorting, and endocytosis, cycling through different cellular environments with varying acidity.
- The crystal structure of sortilin was analyzed at pH 5.5, similar to the acidic conditions of late endosomes, and showed notable distortion in its 10-bladed β-propeller domain.
- The research found that this distortion, along with the formation of pH-dependent dimers, blocks ligand binding sites, explaining how pH affects sortilin's ability to interact with its ligands.
Article Abstract
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.
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| http://dx.doi.org/10.1016/j.str.2017.09.015 | DOI Listing |
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