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SorLA Vps10p domain in ligand-free formSorLA Vps10p domain in ligand-free form
Structural highlights
FunctionSORL_HUMAN Likely to be a multifunctional endocytic receptor, that may be implicated in the uptake of lipoproteins and of proteases. Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. Binds the receptor-associated protein (RAP). Could play a role in cell-cell interaction. Publication Abstract from PubMedSorLA 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-beta (Abeta) peptides by directly binding Abeta. Here, we determined the crystal structure of the human sorLA domain responsible for Abeta capture, Vps10p, in an unbound state and in complex with two ligands. Vps10p assumes a ten-bladed beta-propeller fold with a large tunnel at the center. An internal ligand derived from the sorLA propeptide bound inside the tunnel to extend the beta-sheet of one of the propeller blades. The structure of the sorLA Vps10p-Abeta 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 beta-sheet formation. Structural basis for amyloidogenic peptide recognition by sorLA.,Kitago Y, Nagae M, Nakata Z, Yagi-Utsumi M, Takagi-Niidome S, Mihara E, Nogi T, Kato K, Takagi J Nat Struct Mol Biol. 2015 Mar;22(3):199-206. doi: 10.1038/nsmb.2954. Epub 2015, Feb 2. PMID:25643321[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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