Title
Conformation-Dependent Manipulation of Human Islet Amyloid Polypeptide Fibrillation by Shiitake-Derived Lentinan
Author
Yanru Xin, Xiuxia Wang, Liang Luo, Fanling Meng
Year
2018
Journal
ACS Applied Materials & Interfaces
Abstract
Misfolding and aggregation of human islet amyloid polypeptide (hIAPP) into fibrils is an important contribution 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 than the inter-molecular binding of hIAPP, which redirects hIAPP aggregates to discrete nontoxic nanocomposites. To the best of our knowledge, this is the first time to report a conformation-dependent inhibition of hIAPP aggregation, which will provide new insights for our understanding of the manipulation mechanisms on hIAPP by natural polysaccharides, and open a new avenue for designing and screening potential amyloid inhibitors against type 2 diabetes.
Full Article
Instrument
J-810
Keywords
Circular dichroism, Secondary structure, Chemical stability, Membrane interactions, Aggregation, Biochemistry