Abstract
Human islet amyloid polypeptide (hIAPP) corresponds to a 37-residue hormone present in insulin granules that maintains a high propensity to form β-sheet structures during co-secretion with insulin. Previously, employing a biomimetic approach, we proposed a panel of optimized IAPP sequences with only one residue substitution that shows the capability to reduce amyloidogenesis. Taking into account that specific membrane lipids have been considered as a key factor in the induction of cytotoxicity, in this study, following the same design strategy, we characterize the effect of a series of lipids upon several polypeptide domains that show the highest aggregation propensity. The characterization of the C-native segment of hIAPP (residues F23-Y37), together with novel variants F23R and I26A allowed us to demonstrate an effect upon the formation of β-sheet structures. Our results suggest that zwitterionic phospholipids promote adsorption of the C-native segments at the lipid-interface and β-sheet formation with the exception of the F23R variant. Moreover, the presence of cholesterol did not modify this behavior, and the β-sheet structural transitions were not registered when the N-terminal domain of hIAPP (K1-S20) was characterized. Considering that insulin granules are enriched in phosphatidylserine (PS), the property of lipid vesicles containing negatively charged lipids was also evaluated. We found that these types of lipids promote β-sheet conformational transitions in both the C-native segment and the new variants. Furthermore, these PS/peptides arrangements are internalized in Langerhans islet β-cells, localized in the endoplasmic reticulum, and trigger critical pathways such as unfolded protein response (UPR), affecting insulin secretion. Since this phenomenon was associated with the presence of cytotoxicity on Langerhans islet β-cells, it can be concluded that the anionic lipid environment and degree of solvation are critical conditions for the stability of segments with the propensity to form β-sheet structures, a situation that will eventually affect the structural characteristics and stability of IAPP within insulin granules, thus modifying the insulin secretion.
Highlights
Human islet amyloid polypeptide is a hormone that slows down gastric emptying and participates in the regulation of plasmatic glucose associated with functions such as glucagon-release inhibition and leptin sensitization [1,2]. hIAPP is a monomeric peptide processed in the Golgi complex and secreted in insulin granules in response to β-cell secretagogues [3]
During the course of the present investigation, employing a biomimetic approach, we have been able to develop and evaluate new variants of IAPP with the property to show fewer propensities to form β-sheet structures. New sequences such as F23R have shown to increase the stability of the C-native segment of IAPP, with an important involvement of the anionic nature lipids. This behavior can be associated at pH 7.4 with charged lipids that contributed to structural changes towards the β-sheet formation, whereas the I26A variant shows a neutral charge and an isoelectric point similar to the C-native segment, promoting a strong interaction with anionic phospholipids
The content of anionic phospholipids in β-cell membranes is reported to range from 2.5% to 13.2%, a proportion mainly situated in the inner leaflet of the membrane [38], proportion much similar as found in insulin secretory granules where a higher content of PS and phosphatidylinositol has been described [17,42], which are derived from endoplasmic reticulum (ER) membranes during insulin maturation
Summary
Human islet amyloid polypeptide (hIAPP) is a hormone that slows down gastric emptying and participates in the regulation of plasmatic glucose associated with functions such as glucagon-release inhibition and leptin sensitization [1,2]. hIAPP is a monomeric peptide processed in the Golgi complex and secreted in insulin granules in response to β-cell secretagogues [3]. Several variants of hIAPP modify their stability accelerating amyloid formation; for instance, in Asian populations, the S20G mutation has been associated with early-stage cases of DM2 [4]. Rat IAPP (rIAPP) containing structural differences with hIAPP in six residues situated in region 18–29 (H18R, F23L, A25P, I26V, S28P, and S29P) show a diminished trend to produce amyloid fibrils [6]. These changes allowed the development of pramlintide, an amylinomimetic peptide with three variants (A25P, S28P, and S29P) used in DM2 therapy; the propensity to aggregation of this sequence is not completely avoided
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