Lipid Modulation in the Formation of β-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on β-Cell Homeostasis

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.

eIF4A/PDCD4 Pathway, a Factor for Doxorubicin Chemoresistance in a Triple-Negative Breast Cancer Cell Model

“…In variant B, we identified a strong activation of binding immunoglobulin protein (BiP), a UPR chaperone master regulator ( Figure 1 F,G). This was consistent with one of our previous studies, in which metabolic inflammation induced ER stress [ 48 ]. Chaperones such as heat shock proteins are associated with key cancer hallmarks such as cell proliferation, invasion, and metastasis [ 49 ].…”

Impact of cholesterol-pathways on breast cancer development, a metabolic landscape

“…Nowadays, there is increasing evidence of the role of lipid metabolism alterations as biomarkers of cancer prognosis and survival [9]. Changes of expression of Ivyspring International Publisher lipid-metabolism genes are found in several tumors, considering lipid metabolism modulates cellular processes range from plasmatic and organelle membrane organization and plasticity [10,11], ATP production [12], to intracellular signaling alterations [13,14].…”

Synthesis of Aza-BODIPYs, Their Differential Binding for Cu(II), and Results of Bioimaging as Fluorescent Dyes of Langerhans β-Cells

“…The culture conditions were at a temperature of 37 °C and a 5% CO 2 humidified atmosphere, according to the previous protocols. 33 , 34 , 43 …”

“…Penicillin (50 U/mL) and streptomycin (50 μg/L) were added to the media. The culture conditions were at a temperature of 37 °C and a 5% CO 2 humidified atmosphere, according to the previous protocols. ,, …”