scholarly journals Bleomycin modulates amyloid aggregation in β-amyloid and hIAPP

RSC Advances ◽  
2020 ◽  
Vol 10 (43) ◽  
pp. 25929-25946 ◽  
Author(s):  
Anchala Kumari ◽  
Ritika Sharma ◽  
Nidhi Shrivastava ◽  
Pallavi Somvanshi ◽  
Abhinav Grover
Keyword(s):  
Islet Amyloid Polypeptide ◽  
Amyloid Β ◽  
Human Islet ◽  
Amyloid Aggregation ◽  
Islet Amyloid ◽  
Dual Inhibitor ◽  
Human Islet Amyloid Polypeptide ◽  
Β Amyloid ◽  
Β Sheet

Bleomycin acts as a dual inhibitor against both amyloid β and human islet amyloid polypeptide by binding to the β-sheet grooves considered as the amyloids hotspot.

scholarly journals Human Islet Amyloid Polypeptide Fibril Binding to Catalase: A Transmission Electron Microscopy and Microplate Study

2010 ◽  
Vol 10 ◽  
pp. 879-893 ◽  
Author(s):  
Nathaniel G. N. Milton ◽  
J. Robin Harris
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Β ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Transmission Electron

The diabetes-associated human islet amyloid polypeptide (IAPP) is a 37-amino-acid peptide that forms fibrilsin vitroandin vivo. Human IAPP fibrils are toxic in a similar manner to Alzheimer's amyloid-β (Aβ) and prion protein (PrP) fibrils. Previous studies have shown that catalase binds to Aβ fibrils and appears to recognize a region containing the Gly-Ala-Ile-Ile sequence that is similar to the Gly-Ala-Ile-Leu sequence found in human IAPP residues 24-27. This study presents a transmission electron microscopy (TEM)—based analysis of fibril formation and the binding of human erythrocyte catalase to IAPP fibrils. The results show that human IAPP 1-37, 8-37, and 20-29 peptides form fibrils with diverse and polymorphic structures. All three forms of IAPP bound catalase, and complexes of IAPP 1-37 or 8-37 with catalase were identified by immunoassay. The binding of biotinylated IAPP to catalase was high affinity with a KDof 0.77nM, and could be inhibited by either human or rat IAPP 1-37 and 8-37 forms. Fibrils formed by the PrP 118-135 peptide with a Gly-Ala-Val-Val sequence also bound catalase. These results suggest that catalase recognizes a Gly-Ala-Ile-Leu—like sequence in amyloid fibril-forming peptides. For IAPP 1-37 and 8-37, the catalase binding was primarily directed towards fibrillar rather than ribbon-like structures, suggesting differences in the accessibility of the human IAPP 24-27 Gly-Ala-Ile-Leu region. This suggests that catalase may be able to discriminate between different structural forms of IAPP fibrils. The ability of catalase to bind IAPP, Aβ, and PrP fibrils demonstrates the presence of similar accessible structural motifs that may be targets for antiamyloid therapeutic development.

scholarly journals 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

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1201 ◽  
Author(s):  
Israel Martínez-Navarro ◽  
Raúl Díaz-Molina ◽  
Angel Pulido-Capiz ◽  
Jaime Mas-Oliva ◽  
Ismael Luna-Reyes ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Membrane Lipids ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Insulin Granules ◽  
The Impact ◽  
Β Sheet

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.

2D amyloid aggregation of human islet amyloid polypeptide at the solid–liquid interface

Soft Matter ◽  
2012 ◽  
Vol 8 (5) ◽  
pp. 1616-1622 ◽  
Author(s):  
Ye-Ping Yu ◽  
Shuai Zhang ◽  
Qian Liu ◽  
Yan-Mei Li ◽  
Chen Wang ◽  
...  
Keyword(s):  
Islet Amyloid Polypeptide ◽  
Liquid Interface ◽  
Human Islet ◽  
Amyloid Aggregation ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Solid Liquid Interface ◽  
Solid Liquid

scholarly journals Common fibrillar spines of amyloid-β and human islet amyloid polypeptide revealed by microelectron diffraction and structure-based inhibitors

2017 ◽  
Vol 293 (8) ◽  
pp. 2888-2902 ◽  
Author(s):  
Pascal Krotee ◽  
Sarah L. Griner ◽  
Michael R. Sawaya ◽  
Duilio Cascio ◽  
Jose A. Rodriguez ◽  
...  
Keyword(s):  
Islet Amyloid Polypeptide ◽  
Amyloid Β ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

scholarly journals Time dependence of NMR observables reveals salient differences in the accumulation of early aggregated species between human islet amyloid polypeptide and amyloid-β

2018 ◽  
Vol 20 (14) ◽  
pp. 9561-9573 ◽  
Author(s):  
Anaïs R. F. Hoffmann ◽  
Lucie Caillon ◽  
Lilian Shadai Salazar Vazquez ◽  
Pierre-Alexandre Spath ◽  
Ludovic Carlier ◽  
...  
Keyword(s):  
Time Dependence ◽  
Islet Amyloid Polypeptide ◽  
Proton Nmr ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Proton NMR shows that IAPP fibril formation does not involve the accumulation of early aggregated species, in contrast with Aβ.

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