SorLA Vps10p domain directly recognizes Amyloid-β peptide

SorLA is a single-pass transmembrane protein containing a large (~2,000 a.a) multi-domain extracellular region. It is abundantly expressed in neurons while its physiological function is still incompletely understood. SorLA has been known to be genetically linked with Alzheimer's disease (AD) and its protein level is reduced in the brain of some AD patients [1]. It was reported that sorLA directly interacts with amyloid precursor protein (APP), a precursor of the pathogenic amyloid-β (Aβ) peptide, through its LA domain [2], which led to a hypothesis that sorLA would re-route APP away from the amyloidogenic pathway. Previously, we reported that sorLA directly binds to Aβ peptide via the Vps10p domain and plays an important role in the catabolism Aβ clearance in living cells [3]. We also determined the structure of Vps10p domain of sorLA, both as ligand free form and as a complex with its own propeptide. Our structural and functional study strongly suggest that sorLA Vps10p domain may play a central role in its Aβ-lowering function in neurons. In the current study, we obtained the structure of human sorLA Vps10p domain in complex with Aβ peptide fragment, and identified the Aβ peptide binding site at the inner tunnel of the β-propeller fold. 2 Experiment