Dynamics of the conformational transitions during the dimerization of an intrinsically disordered peptide: a case study on the human islet amyloid polypeptide fragment

2016 ◽  
Vol 18 (43) ◽  
pp. 29892-29904 ◽  
Author(s):  
Qin Qiao ◽  
Ruxi Qi ◽  
Guanghong Wei ◽  
Xuhui Huang
Keyword(s):  
Molecular Dynamics ◽  
Islet Amyloid Polypeptide ◽  
Conformational Transitions ◽  
Human Islet ◽  
Islet Amyloid ◽  
Intrinsically Disordered ◽  
Human Islet Amyloid Polypeptide ◽  
Intrinsically Disordered Peptide ◽  
Dynamics Simulations

Dimerization pathways of the human islet amyloid polypeptide fragment are elucidated from extensive molecular dynamics simulations.

Zinc-Induced Conformational Transitions in Human Islet Amyloid Polypeptide and Their Role in the Inhibition of Amyloidosis

2018 ◽  
Vol 122 (43) ◽  
pp. 9852-9859 ◽  
Author(s):  
Alexandre I. Ilitchev ◽  
Maxwell J. Giammona ◽  
Jurgen N. Schwarze ◽  
Steven K. Buratto ◽  
Michael T. Bowers
Keyword(s):  
Islet Amyloid Polypeptide ◽  
Conformational Transitions ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

scholarly journals β-Hairpin Peptide Mimics Decrease Human Islet Amyloid Polypeptide (hIAPP) Aggregation

2021 ◽  
Vol 9 ◽  
Author(s):  
Jacopo Lesma ◽  
Faustine Bizet ◽  
Corentin Berardet ◽  
Nicolo Tonali ◽  
Sara Pellegrino ◽  
...  
Keyword(s):  
Rational Design ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Disordered Proteins ◽  
Diabetic Patients ◽  
Amyloid Β Peptide ◽  
Aggregation Process ◽  
Islet Amyloid ◽  
Intrinsically Disordered ◽  
Human Islet Amyloid Polypeptide

Amyloid diseases are degenerative pathologies, highly prevalent today because they are closely related to aging, that have in common the erroneous folding of intrinsically disordered proteins (IDPs) which aggregate and lead to cell death. Type 2 Diabetes involves a peptide called human islet amyloid polypeptide (hIAPP), which undergoes a conformational change, triggering the aggregation process leading to amyloid aggregates and fibers rich in β-sheets mainly found in the pancreas of all diabetic patients. Inhibiting the aggregation of amyloid proteins has emerged as a relevant therapeutic approach and we have recently developed the design of acyclic flexible hairpins based on peptidic recognition sequences of the amyloid β peptide (Aβ1–42) as a successful strategy to inhibit its aggregation involved in Alzheimer’s disease. The present work reports the extension of our strategy to hIAPP aggregation inhibitors. The design, synthesis, conformational analyses, and biophysical evaluations of dynamic β-hairpin like structures built on a piperidine-pyrrolidine β-turn inducer are described. By linking to this β-turn inducer three different arms (i) pentapeptide, (ii) tripeptide, and (iii) α/aza/aza/pseudotripeptide, we demonstrate that the careful selection of the peptide-based arms from the sequence of hIAPP allowed to selectively modulate its aggregation, while the peptide character can be decreased. Biophysical assays combining, Thioflavin-T fluorescence, transmission electronic microscopy, capillary electrophoresis, and mass spectrometry showed that the designed compounds inhibit both the oligomerization and the fibrillization of hIAPP. They are also capable to decrease the aggregation process in the presence of membrane models and to strongly delay the membrane-leakage induced by hIAPP. More generally, this work provides the proof of concept that our rational design is a versatile and relevant strategy for developing efficient and selective inhibitors of aggregation of amyloidogenic proteins.

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