A new polymorphism of human amylin fibrils with similar protofilaments and a conserved core

Li, Dongyu; Zhang, Xueli; Wang, Youwang; Zhang, Haonan; Song, Kai; Bao, Keyan; Zhu, Ping

doi:10.1016/j.isci.2022.105705

Cited by 8 publications

(7 citation statements)

References 47 publications

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“…Similar β-hairpin structures were observed in our previous studies on the hIAPP dimer assembly as well as the DMD simulations on the hIAPP oligomeric aggregation by Sun et al, implying the formation of the protofibril precursor in the oligomerization. Notably, Cryo-EM structures of patient extract-seeded hIAPP fibrils display twisting features, and the full-length cryo-EM structures of hIAPP fibrils in a salt-free environment contain three β-sheets . All of these differences may be derived from the various incubation conditions …”

Section: Results and Discussionmentioning

confidence: 99%

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: β-Protofibril Formed by β-Hairpin Lateral or Longitudinal Association

et al. 2023

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The fibrillar protein deposits of the human islet amyloid polypeptide (hIAPP) in the pancreatic islet of Langerhans are pathological hallmark of type II diabetes. Extensive experimental studies have revealed that the oligomeric formations of the hIAPP are more toxic than the mature fibrils. Exploring the oligomeric conformations in the early aggregation state is valuable for effective therapeutics. In this work, using the all-atom explicit-solvent replica exchange molecular dynamic (REMD) simulations, we investigated the structural features and the assembly mechanisms of the full-length hIAPP trimer in solution.The hIAPP trimer adopted more β-sheets than a-helix conformations, and three types of ordered conformations including open β-barrel, single-layer, and doublelayer U-shaped β-sheet structures with five β-strands were captured in our simulations. A representative single-layer β-sheet conformation with a CCS value of 1400 Å 2 in our simulations matches exactly the experimentally ESI-IMS-MS-derived hIAPP trimer sample. These five β-strand conformations formed via the β-hairpin lateral and longitudinal association, respectively, showing two βprotofibril formation models. To the best of our knowledge, it is the first time to reveal two routes to β-sheet formation in the hIAPP trimers on the atomic level. The contact probabilities between pairs of the β-stranded residue show that the hydrophobic interactions between the residues F 15 ∼ V 17 and A 25 ∼ L 27 are responsible for the inter-and intra-peptide β-hairpin formations. All of these results indicate that the β-sheet formation is the first step in the conformational changes toward pathological aggregation and provides evidence of the β-sheet assembly mechanism into hIAPP aggregation.

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Section: Results and Discussionmentioning

confidence: 99%

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: β-Protofibril Formed by β-Hairpin Lateral or Longitudinal Association

et al. 2023

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“…(C) Cryo-EM structures of fibrils of hIAPP derived from a synthetic peptide (PDB:7YKW, left) and fibrils seeded with isolated aggregates from pancreas of diabetic patients (PDB: 7M61, right). 27,92,93 (Fig. 3C).…”

Section: Copper and Iapp Amyloid Aggregationmentioning

confidence: 94%

“…3C). 90,92–94 The structural features of amyloid fibrils seeded by patient-extracted fibrils (Fig. 3C, right) are distinct from those of fibrils grown in vitro from the synthetic peptide (Fig.…”

Section: Introductionmentioning

confidence: 98%

Copper binding and protein aggregation: a journey from the brain to the human lens

Posadas,

Sánchez-López,

Quintanar

2023

RSC Chem. Biol.

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“…In a very recent study that was carried out in the absence of salt and under conditions of 2% HFIP, a hIAPP fibril structure is obtained in which some parts of the N-terminus of the peptide could be refined in the electron densities. 77 The basic unit is built from an asymmetric dimer, which would result in two sets of NMR resonances. We assume that under conditions of low salt and in the presence of HFIP a different polymorph is obtained that is not consistent with our solidstate NMR results. )…”

Section: ■ Introductionmentioning

confidence: 99%

Structural Insights into Seeding Mechanisms of hIAPP Fibril Formation

Suladze,

Sustay Martinez,

Rodriguez Camargo

et al. 2024

J. Am. Chem. Soc.

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The deposition of islet amyloid polypeptide (hIAPP) fibrils is a hallmark of β-cell death in type II diabetes. In this study, we employ state-of-the-art MAS solid-state spectroscopy to investigate the previously elusive N-terminal region of hIAPP fibrils, uncovering both rigidity and heterogeneity. Comparative analysis between wild-type hIAPP and a disulfide-deficient variant (hIAPPC2S,C7S) unveils shared fibril core structures yet strikingly distinct dynamics in the N-terminus. Specifically, the variant fibrils exhibit extended β-strand conformations, facilitating surface nucleation. Moreover, our findings illuminate the pivotal roles of specific residues in modulating secondary nucleation rates. These results deepen our understanding of hIAPP fibril assembly and provide critical insights into the molecular mechanisms underpinning type II diabetes, holding promise for future therapeutic strategies.

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A new polymorphism of human amylin fibrils with similar protofilaments and a conserved core

Cited by 8 publications

References 47 publications

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: β-Protofibril Formed by β-Hairpin Lateral or Longitudinal Association

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: β-Protofibril Formed by β-Hairpin Lateral or Longitudinal Association

Copper binding and protein aggregation: a journey from the brain to the human lens

Structural Insights into Seeding Mechanisms of hIAPP Fibril Formation

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