title: Dissecting the role of single regions of an IAPP mimic and IAPP in inhibition of Aβ40 amyloid formation and cytotoxicity.
abstract: Alzheimer's disease (AD) and type 2 diabetes (T2D) are linked to the self-association of β-amyloid peptide (Aβ) and islet amyloid polypeptide (IAPP), respectively. We have shown that IAPP-GI, a soluble IAPP analogue and mimic of nonamyloidogenic and nontoxic IAPP, binds Aβ with high affinity and blocks its cytotoxic self-assembly and fibrillogenesis. We have also shown that IAPP and Aβ interact with each other into nonfibrillar and nontoxic heterocomplexes that suppress cytotoxic self-association by both polypeptides. The Aβ-IAPP interaction might thus be a molecular link between AD and T2D. We studied the role of individual IAPP-GI and IAPP regions in their inhibitory function on Aβ40 self-association and cytotoxicity. We found that the presence of the two hot-spot regions of the Aβ-IAPP interaction interface in IAPP(8-28) is not sufficient for inhibitory function and that, in addition to IAPP(8-28), the presence of the N-terminal region IAPP(1-7) is absolutely required. By contrast, the C-terminal region, IAPP(30-37), is not required although its presence together with IAPP(1-7) in IAPP-GI results in a marked enhancement of the inhibitory effect as compared to IAPP(1-28)-GI. We suggest that the inhibitory effect of IAPP-GI and IAPP on Aβ40 fibrillogenesis and cell toxicity is mediated primarily by interactions involving the hot regions of the Aβ-IAPP interaction interface and the N terminus of IAPP while a concerted and likely structure-stabilizing action of the N- and C-terminal IAPP regions potentiates this effect. These results identify important molecular determinants of the amyloid suppressing function of the Aβ40-IAPP interaction and could contribute to the design of novel inhibitors of Aβ40 aggregation and cell degeneration.
authors.affiliation: Division of Peptide Biochemistry, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Erika
authors.initials: E
authors.lastname: Andreetto
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Yan
authors.forename: Andrea
authors.initials: A
authors.lastname: Caporale
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Kapurniotu
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000235:genetics / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D002942:Circular Dichroism; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000633:toxicity; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000235:genetics / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013050:Spectrometry, Fluorescence
chemical_list: C509234:(N-Me)G24, (N-Me)I26-IAPP; D000682:Amyloid; D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D009842:Oligopeptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)