Linking hIAPP misfolding and aggregation with type 2 diabetes mellitus: a structural perspective

Hassan, Shahab; White, Kenneth; Terry, Cassandra

doi:10.1042/bsr20211297

Cited by 8 publications

(5 citation statements)

References 172 publications

(218 reference statements)

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“…These critical seeds have the ability to mature into beta-sheet rich fibrils as well as interact with monomers and promote their aggregation through a phenomenon referred to as self-seeding (65). Rationale behind Amylin protein selection is that it is a hallmark of type-2 diabetes (T2D), another well-studied protein misfolding disease (66). A positive correlation between diabetes and flaviviral infection has also been reported by many (67).…”

Section: Fibrillogenesis Is Enhanced By Membrane-mimicking Liposomes ...mentioning

confidence: 99%

Japanese Encephalitis Virus: A pan-proteome analysis for aggregation propensities and in vitro validation with Capsid anchor and 2K peptide

Saumya,

Bharadwaj,

Thakur

et al. 2023

Preprint

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Japanese encephalitis infection is a vector-borne disease caused by the flavivirus Japanese encephalitis virus (JEV). It is responsible for severe brain infections in humans worldwide. Given the ubiquitous nature of complications and tropism associated with Japanese encephalitis (JE) infection, a holistic understanding of its molecular mechanism is essential. The phenomenon of abnormal protein aggregation into pathogenic amyloids is now increasingly linked to multiple human diseases, also known as Amyloidosis. Most are neurodegenerative disorders, but amyloidosis is not restricted to a specific organ or tissue type. The overlap of viral protein aggregation with human pathologies remains limited, and it is gaining momentum, especially after the devastating Covid-19 pandemic. Therefore, in this study, we have examined the likelihood of aggregation for the entire collection of proteins in JEV. Multiple independent web server tools were employed to scan for potential amyloid-prone regions (APRs), and it was followed by in vitro validation using two JEV transmembrane domains, Capsid anchor, and 2K peptides. These synthetic viral peptides were introduced to artificial aggregation-inducing conditions and then analyzed using different dye-based assays and microscopy methods confirming amyloid-like fibril structure formation. We found these aggregates cytotoxic to human neuronal cell lines and membrane damaging to human blood-derived RBCs. The aggregation kinetics of both peptides is enhanced in the presence of artificial membrane models and seeds of self and diabetes hallmark protein Amylin. Our findings thereby strongly suggest the possibility of JEV protein aggregation playing a vital role in its pathogenesis, opening up a broad scope of future study. Also, the interplay between JEV protein aggregation and initiation/progression of other proteopathies is possible and needs further exploration.

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Section: Fibrillogenesis Is Enhanced By Membrane-mimicking Liposomes ...mentioning

confidence: 99%

Japanese Encephalitis Virus: A pan-proteome analysis for aggregation propensities and in vitro validation with Capsid anchor and 2K peptide

Saumya,

Bharadwaj,

Thakur

et al. 2023

Preprint

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“…2,3 In this work, we focus on the neuroendocrine peptide hormone human islet amyloid polypeptide (hIAPP) that is found to be aggregated in amyloidogenic plaques in individuals suffering from type 2 diabetes (T2DM). 4 Under conditions of hyperglycemia, the secretion of insulin and hIAPP are upregulated with a disproportionate increase of hIAPP. 5 Increased secretion of hIAPP in severe hyperglycemia has been suggested to facilitate the formation of hIAPP derived amyloid deposits and pancreatic islet β-cell dysfunction.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In this work, we focus on the neuroendocrine peptide hormone human islet amyloid polypeptide (hIAPP) that is found to be aggregated in amyloidogenic plaques in individuals suffering from type 2 diabetes (T2DM) . Under conditions of hyperglycemia, the secretion of insulin and hIAPP are upregulated with a disproportionate increase of hIAPP .…”

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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“…There are available X-ray structures for many of these segment aggregates (summarized in ref. 53). hIAPP fibrils display the classic high b sheet structure content of amyloids.…”

Section: Introductionmentioning

confidence: 99%

Effect of strand register in the stability and reactivity of crystals from peptides forming amyloid fibrils

Muñoz-Gutiérrez,

Adasme-Carreño,

Alzate-Morales

et al. 2023

Phys. Chem. Chem. Phys.

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Linking hIAPP misfolding and aggregation with type 2 diabetes mellitus: a structural perspective

Cited by 8 publications

References 172 publications

Japanese Encephalitis Virus: A pan-proteome analysis for aggregation propensities and in vitro validation with Capsid anchor and 2K peptide

Japanese Encephalitis Virus: A pan-proteome analysis for aggregation propensities and in vitro validation with Capsid anchor and 2K peptide

Structural Insights into Seeding Mechanisms of hIAPP Fibril Formation

Effect of strand register in the stability and reactivity of crystals from peptides forming amyloid fibrils

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