Conformation-Dependent Manipulation of Human Islet Amyloid Polypeptide Fibrillation by Shiitake-Derived Lentinan

Misfolding and aggregation of human islet amyloid polypeptide (hIAPP) into fibrils are important contributions to the pathology of type 2 diabetes. Developing effective inhibitors of protein aggregation and fibrillation has been considered a promising therapeutic approach to preventing and treating type 2 diabetes. Herein, we report that Shiitake-derived polysaccharide lentinan manipulates in vitro hIAPP fibrillation and modulates IAPP-induced cytotoxicity in a conformation-dependent manner. In its triple-helical conformation, lentinan effectively inhibits hIAPP fibrillation, either in bulk solution or in the presence of lipid membrane, suppresses reactive oxygen species (ROS) generation, and attenuates hIAPP-induced cell toxicity. In contrast, lentinan accelerates hIAPP aggregation when it exists in a random-coil conformation and shows no suppression on hIAPP-mediated ROS production. Further investigation shows that the interaction between triple-helical lentinan and monomeric hIAPP is more favorable tha...