Effect of Post-Translational Amidation on Islet Amyloid Polypeptide Conformational Ensemble: Implications for Its Aggregation Early Steps

Abstract

The human islet amyloid polypeptide (hIAPP) is an intrinsically disordered protein that can self-assemble into fibrillar aggregates that play a key role in the pathogenesis of the type II diabetes mellitus. hIAPP can transiently adopt sans-serifα-helix and sans-serifβ-strand conformations that could be important intermediate species on the fibrillization pathway. However, experimental studies of the monomeric peptide conformations are limited due to its high aggregation propensity, and the early steps of the hIAPP association are not clearly characterized. In particular, the question of whether the aggregation-prone conformation is sans-serifα-helical or sans-serifβ-strand-rich is still debated. In this study, combining extensive all-atom molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulations in explicit water, we shed some light on the differences between the amidated and non-amidated hIAPP conformational ensembles. Our study shows that, when compared to the amidated monomer, the non-amidation of hIAPP induces a significantly lower propensity to form sans-serifβ-strands, especially aggregation-prone sans-serifβ-hairpins. Since the fibrillization of the non-amidated hIAPP is significantly slower than that of the amidated peptide, this indicates that the early steps of the peptide oligomerization involve the association of sans-serifβ-hairpins or sans-serifβ-strands structures.

Histidine Tautomerism Driving Human Islet Amyloid Polypeptide Aggregation in the Early Stages of Diabetes Mellitus Progression: Insight at the Atomistic Level

“…A previous study predicted Rg values between 0.83 to 1.39 nm for the monomeric state of amylin, [32] and another study reported 0.918 nm for the gyration of hIAPP [33] . In addition, in an REMD simulation, an Rg between 0.88 to 0.97 nm was obtained [34] . Therefore, our results are in good agreement with this previous work.…”

Deciphering the Inhibitory Mechanism of hIAPP‐Derived Fragment Peptide Against hIAPP Aggregation in Type 2 Diabetes**

“…[41] The sampling of helical conformation at the N-terminal residues in hIAPP monomer (Figure 6a) is consistent with that of Qiao et al, [51] which reported that residues 4-7 in the N-terminal region of hIAPP monomer displayed notable α-helical propensity in the conformational ensemble generated by extensive MD simulations. After 60 ns, the β-sheet conformation was mainly observed in N-terminal (region 2-4) and C-terminal residues (Ser34 and Asn35), which is consistent with the results reported by Tran et al [52] In the hIAPP-ANFLVH complex, the percentage population of the helix, turn, coil, and bend conformations were 41 � 3.37 %, 18 � 1.5 %, 30 � 2.52 %, and 9 � 0.79 %, respectively, and complete absence of β-sheet was observed ( Figure S4, Table 2). The absence of β-sheet structures in the conformational ensemble of the hIAPP-ANFLVH complex is consistent with circular dichroism (CD) results, which highlighted the prevention of the formation of β-sheet in hIAPP on the addition of ANFLVH peptide at equimolar or higher concentrations.…”

PAM haploinsufficiency does not accelerate the development of diet- and human IAPP-induced diabetes in mice

“…To determine whether PAM haploinsufficiency has an impact on islet amyloid formation and diabetes susceptibility, we crossed mice with beta cell expression of hIAPP with Pam +/− mice. IAPP is a PAM substrate and synthetic hIAPP variants with a free (nonamidated) COOH-terminus aggregate more slowly than COOH-terminally amidated forms [17,40]. We hypothesised that impaired amidation of hIAPP in Pam +/− mice may lead to production of hIAPP forms with altered fibril-forming kinetics, morphology and cytotoxicity [41].…”

“…Human, but not rodent, IAPP aggregates to form islet amyloid deposits in type 2 diabetes, likely contributing to islet inflammation and beta cell failure [14][15][16]. It is plausible that PAMmediated IAPP amidation could alter IAPP aggregation kinetics and, by extension, that PAM deficiency could influence IAPP-related islet pathology [17].…”