Elucidation of 3D Structure of Protein That Can Eliminate Alzheimer’s Disease-Causing Agent

Elucidation of 3D Structure of Protein That Can Eliminate Alzheimer’s Disease-Causing Agent

Feb 3, 2015

SorLA/LR11 is a unique neuronal sorting receptor considered to be a major genetic risk factor for Alzheimer’s disease. We have recently reported that it directs lysosomal targeting of nascent neurotoxic amyloid-b (Ab) peptides by directly binding Ab. Here, we determined the crystal structure of the Vps10p domain from human sorLA, a domain responsible for Ab capture. Structures for unbound sorLA and two ligand bound states were obtained. The sorLA Vps10p domain assumes a 10-bladed b-propeller fold with a large tunnel at the center. An internal ligand derived from the sorLA propeptide bound inside the tunnel to extend the b-sheet of one of the propeller blades. SorLA Vps10p-Ab complex structure 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, suggesting a broad specificity toward peptides with a b-sheet forming propensity.

Figure 1. 3D structure of sorLA Vps10p domain (rainbow) in complex with Aβ (magenta)

Figure 2. The "cross β structure" typically found in amyloid fibers

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