biostudies-literatureCao PNIDDK NIH HHSNIGMS NIH HHS19279-84https://www.ebi.ac.uk/biostudies/studies/S-EPMC3845181biostudies-literatureUnknown110(48)Islet amyloid polypeptide (IAPP) is responsible for amyloid formation in type 2 diabetes and contributes to the failure of islet cell transplants, however the mechanisms of IAPP-induced cytotoxicity are not known. Interactions with model anionic membranes are known to catalyze IAPP amyloid formation in vitro. Human IAPP damages anionic membranes, promoting vesicle leakage, but the features that control IAPP-membrane interactions and the connection with cellular toxicity are not clear. Kinetic studies with wild-type IAPP and IAPP mutants demonstrate that membrane leakage is induced by prefibrillar IAPP species and continues over the course of amyloid formation, correlating additional membrane disruption with fibril growth. Analyses of a set of designed mutants reveal that membrane leakage dProceedings of the National Academy of Sciences of the United States of AmericaIslet amyloid polypeptide toxicity and membrane interactions.PMC3845181GM078114R01 GM078114F32 DK089734F32 DK089734-02Schmidt AMZhang XRaleigh DPWang HCao PAbedini ATu LHfalseIslet amyloid polypeptide toxicity and membrane interactions.Islet amyloid polypeptide (IAPP) is responsible for amyloid formation in type 2 diabetes and contributes to the failure of islet cell transplants, however the mechanisms of IAPP-induced cytotoxicity are not known. Interactions with model anionic membranes are known to catalyze IAPP amyloid formation in vitro. Human IAPP damages anionic membranes, promoting vesicle leakage, but the features that control IAPP-membrane interactions and the connection with cellular toxicity are not clear. Kinetic studies with wild-type IAPP and IAPP mutants demonstrate that membrane leakage is induced by prefibrillar IAPP species and continues over the course of amyloid formation, correlating additional membrane disruption with fibril growth. Analyses of a set of designed mutants reveal that membrane leakage d2013-01-01T00:00:00Z2013 Nov2025-05-29T16:30:51.559Z2025-05-29T16:30:51.559ZS-EPMC38451812421860710.1073/pnas.1305517110