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Nat Struct Mol Biol. 2015 Mar;22(3):199-206. doi: 10.1038/nsmb.2954. Epub 2015 Feb 2.

Structural basis for amyloidogenic peptide recognition by sorLA.

Author information

1
Institute for Protein Research, Osaka University, Suita, Japan.
2
1] Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, Japan. [2] Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
3
Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.

Abstract

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 (Aβ) peptides by directly binding Aβ. Here, we determined the crystal structure of the human sorLA domain responsible for Aβ 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-Aβ 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.

PMID:
25643321
DOI:
10.1038/nsmb.2954
[Indexed for MEDLINE]

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