Amyloid Fiber Formation and Membrane Disruption are Separate Processes Localized in Two Distinct Regions of IAPP, the Type-2-Diabetes-Related Peptide

Abstract

Aggregation of Islet Amyloid Polypeptide (IAPP) has been implicated in the development of type II diabetes. Because IAPP is a highly amyloidogenic peptide, it has been suggested that the formation of IAPP amyloid fibers causes disruption of the cellular membrane and is responsible for the death of β-cells during type II diabetes. Previous studies have shown that the N-terminal 1-19 region, rather than the amyloidogenic 20-29 region, is primarily responsible for the interaction of the IAPP peptide with membranes. Liposome leakage experiments presented in this study confirm that the pathological membrane disrupting activity of the full-length hIAPP is also shared by hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] . The hIAPP 1-19 fragment at a low concentration of peptide induces membrane disruption to a near identical extent as the full-length peptide. At higher peptide concentrations, the hIAPP 1-19 fragment induces a greater extent of membrane disruption than the full-length peptide. Similar to the full-length peptide, hIAPP 1-19 exhibits a random coil conformation in solution and adopts an α-helical conformation upon binding to lipid membranes. However, unlike the full-length peptide, the hIAPP 1-19 fragment did not form amyloid fibers when incubated with POPG vesicles. These results indicate that membrane disruption can occur independently from amyloid formation in IAPP, and the sequences responsible for amyloid formation and membrane disruption are located in different regions of the peptide.

Islet amyloid polypeptide toxicity and membrane interactions

“…The importance of postion-18 is consistent with NMR studies of IAPP fragments in the presence of model membranes (45). hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and rIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] , which differ only in the identity of residue-18, bind membranes in different orientations, and these differences are believed to correlate with the difference in the potential for membrane disruption (45,46). In summary, our data dissociate IAPP-induced leakage of standard model membranes from direct cellular toxicity, thereby indicating that further studies to identify the precise mechanism (s) of IAPP cellular toxicity are essential for the optimal development of therapeutic strategies to prevent T2D and islet graft failure.…”

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

“…Our present work supports p3 and N9 channel-mediated toxicity and suggests that ion channel blocking strategies for these smaller amyloid fragments may present an important therapeutic avenue for treatments for sporadic AD and Down syndrome. Our work has far broader relevance beyond the boundaries of amyloid-related neurodegenerative diseases (43). The discovery that nonamyloidogenic peptides may be pathogenic when oligomerized and embedded in membranes is startling and may require a reevaluation of the pathophysiology of these diseases.…”

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

“…Moreover, it was reported that the amino acid sequences responsible for amyloid formation and membrane disruption are located in different regions of the peptide and amyloid formation can occur independently from membrane disruption [29,30]. The C-terminal domain has amyloidogenic property, and the N-terminal fragment of hIAPP was alone sufficient to induce membrane perturbation and a single mutation abolished the activity [31][32][33].…”