RT Journal Article
SR Electronic
T1 Zinc Boosts EGCG’s hIAPP Amyloid Inhibition Both in Solution and Membrane
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 401521
DO 10.1101/401521
A1 Young-Ho Lee
A1 Yuxi Lin
A1 Sarah J. Cox
A1 Misaki Kinoshita
A1 Bikash R. Sahoo
A1 Magdalena Ivanova
A1 Ayyalusamy Ramamoorthy
YR 2018
UL http://biorxiv.org/content/early/2018/08/27/401521.abstract
AB Amyloid aggregation of human islet amyloid polypeptide (hIAPP) is linked to insulin-producing islet cell death in type II diabetes. Previous studies have shown the amyloid inhibiting effects of zinc (Zn) and insulin that are co-present with hIAPP in islet cells, and the lipid membrane has been shown to significantly influence the aggregation kinetics. Increasing number of studies report the importance of developing small molecule inhibitors to suppress the hIAPP’s toxicity. Particularly, the ability of epigallocatechin-gallate (EGCG) to inhibit amyloid aggregation of a variety of amyloid peptide/proteins including hIAPP initiated numerous studies including the development of compounds to potentially treat amyloid diseases. In this study, by using a combination of thioflavin-T fluorescence and transmission electron microscopy experiments, we demonstrate a significant enhancement in EGCG’s efficiency, when mixed with Zn, to significantly suppress hIAPP amyloid aggregation both in presence and absence of lipid membrane. Circular dichroism experiments indicate the formation and stabilization of a helical structure of hIAPP in presence of EGCG:Zn complex. Our results also reveal the ability of EGCG or EGCG:Zn to suppress hIAPP’s cellular toxicity and that the ability of EGCG to chelate with Zn suppresses zinc’s cellular toxicity. We suggest that the reported results would be useful to develop strategies to trap hIAPP intermediates for further biophysical and structural studies, and also to devise approaches to abolish amyloid aggregation and cellular toxicity.