巨大受容体sorLAのVps10ドメインによるアミロイドペプチド認識の分子機構

抄録

A giant single-pass trans-membrane receptor, sorLA constructed by over 2,000 amino acid residues has been recognized as a major risk factor for Alzheimerʼs disease (AD) based on reports that its level was reduced in the brains of patients with sporadic AD, and that the increased level of amyloid-β (Aβ), the most major AD causative substance, was observed in the sorLA knockout mice. SorLA can be classified in the low-density lipoprotein receptor (LDLR) family by its domain composition, meanwhile sorLA has a unique Vps10p domain on its N-terminus unlike other LDLR family members. Last year, we discovered that sorLA Vps10p domain specifically recognizes Aβ peptide in our sorLA structural study project, and suggested that sorLA has the function to captures the newly produced Aβ peptide at endosome and dump it to lysosome using its Vps10p domain. Following the discovery, we successfully revealed the crystal structure of sorLA Vps1-p domain for its ligand free form and complexed forms with two kinds of ligand peptides, its own propetide and Aβ peptide fragments. Based on these results combined with biological experiments, we suggested that sorLA Vps10p domain can ʻspecificallyʼ recognize β-aggregation tendency.