Structural basis for amyloidogenic peptide recognition by ​sorLA

SorLA is a neuronal sorting receptor considered to be a major risk factor for Alzheimer’s disease. We have recently reported that it directs lysosomal targeting of nascent neurotoxic ​amyloid-β (​) peptides by directly binding ​. Here, we determined the crystal structure of the human ​sorLA domain responsible for ​ capture, Vps10p, in an unbound state and in complex with two ligands. Vps10p assumes a ten-bladed β-propeller fold with a large tunnel at the center. An internal ligand derived from the ​sorLA propeptide bound inside the tunnel to extend the β-sheet of one of the propeller blades. The structure of the ​sorLA Vps10p-​ complex revealed that the same site is used. Peptides are recognized by ​sorLA Vps10p in redundant modes without strict dependence on a particular amino acid sequence, thus suggesting a broad specificity toward peptides with a propensity for β-sheet formation.

Yu Kitago, Masamichi Nagae, Zenzaburo Nakata, Maho Yagi-Utsumi, Shizuka Takagi-Niidome, Emiko Mihara, Terukazu Nogi, Koichi Kato & Junichi Takagi

For more details; Nature Structural & Molecular Biology (2015)  [doi:10.1038/nsmb.2954]