Membrane Interactions of IAPP

Christensen, Mikkel Hovden; Schiøtt, Birgit

doi:10.1016/j.bpj.2018.11.2649

Cited by 3 publications

(4 citation statements)

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“…Christensen and Schiott combined a coarse-grained model with umbrella sampling and MD simulations to study the binding of hIAPP on ganglioside-rich membranes. 303 Their multi-scale simulations suggest that hIAPP peptides localize in the membrane regions with higher local concentration of gangliosides because electrostatic interactions favour the association of the cationic hIAPP peptides and the anionic headgroup of the gangliosides.…”

Section: Scollo Et Al Investigated Hiapp Insertion In a Popc (Phosphatidylcholine) Bilayer Bymentioning

confidence: 99%

“…A single molecule of IAPP has been simulated in the presence of a lipid bilayer − or without membrane to compare the monomeric state of hIAPP and pIAPP or rIAPP . In μs-long MD simulations Qiao et al observed transient α-helical and β-sheet structures of monomeric hIAPP during adsorption to the surface of a POPG (palmitoyloleoylphosphatidylglycerol) bilayer .…”

Section: High-resolution Structures Of Iappmentioning

confidence: 99%

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Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

et al. 2021

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The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures and aggregation pathways of this hormone. Recent studies have reported on the importance of early oligomeric intermediates, the many roles of their interactions with lipid membrane, pH, insulin and zinc on the mechanism of aggregation of hIAPP. weight reduction was observed. In a phase-1 clinical trial in which AM833 was combined with the GLP-1-agonist Semaglutid, 20 weeks of treatment, participants lost an average of 17.1 % body weight. Overweight and obesity are risk factors for T2D and cardiovascular disease and the presented weight loss exceed reductions observed for GLP-1 and metformin. It should be noted that an IAPP derivative, pramlintide (symlin) is used, in addition to insulin, in patients with insulindependent T1D and T2D that have been difficult to regulate with insulin by a single drug. 42 Cross-correlation with other diseasesEpidemiological studies link diabetes with neurodegenerative diseases, including Alzheimer's disease [43][44][45][46] and Parkinson's disease. [47][48][49] The link is unclear, but the three conditions are multifactorial and have protein aggregation in their pathophysiology in common. If protein aggregation constitutes the link between these diseases, however, still needs to be proven. The Rotterdam study 50 , published in 1999, showed that patients with T2D have an almost doubled risk of developing dementia and Alzheimer's disease (AD). Data from the ULSAM study (Uppsala Longitudinal study of adult men) showed that already a moderate disturbance in the first-phase insulin release at the age of 55 increased the risk of developing AD thirty years later. 51 This suggests that diabetes precedes AD. In fact, another type of diabetes has been proposed [52][53][54] , which is type 3 diabetes (T3DM) which is an AD associated insulin resistance, also described as "brain diabetes phenotype". A considerable number of biophysical studies have shown a close link between the amyloid-forming proteins IAPP and Aβ. [55][56][57][58] IAPP immunoreactivity is present in formic acid brain extracts from patients with AD 59 and exhibited pattern on the western blot ranges from dimers to 16 mers. 60 The laddering pattern suggests that IAPP is present in the Aβ amyloid deposit. Proximity ligation assay (PLA) using two primary antibodies can be applied to determine the co-deposition of proteins. The positive PLA signal obtained after the combination of anti-IAPP and anti-Aβ antibodies points to the co-deposition of IAPP and Aβ in vivo. To confirm that the peptides interact in vivo, hIAPP transgenic mice were injected with preformed fibrils of Aβ followed by high-fat feeding for ten months. 60 Mice injected with preformed Aβ fibrils developed amyloid in 15% of the islets, which is comparable to mice injected with preformed fibrils of proIAPP. In mice injected with preformed IAPP fibrils, IAPP amyloid was found in 24 % of the islets. Control mice injected with fib...

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Section: Scollo Et Al Investigated Hiapp Insertion In a Popc (Phosphatidylcholine) Bilayer Bymentioning

confidence: 99%

Section: High-resolution Structures Of Iappmentioning

confidence: 99%

Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

et al. 2021

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“…However, additional experimental data are needed to propose more accurate models depicting the role of exosomes in IAPP amyloidogenesis and diabetes development. Molecular simulations of membrane-bound hIAPP from different species have been carried out [200][201][202] including the non-toxic, non-amyloidogenic rIAPP [203]. Molecular dynamics (MD) simulations revealed short-lived α-helical and β-sheet structures throughout IAPP adsorption onto an anionic POPG (palmitoyl oleoyl phosphatidylglycerol) surface of a lipid bilayer [201].…”

Section: Iapp-membrane Interactionsmentioning

confidence: 99%

“…Both simulations and experiments demonstrated that IAPP insertion into zwitterionic membranes is assisted by non-vesicular lipids that are present in solution at their critical micellar concentration (cmc). Other authors have adopted coupled coarse-grained/umbrella sampling molecular dynamics simulations to investigate the interactions of hIAPP with ganglioside-rich membranes [200]. These simulations indicate that hIAPP locate in ganglioside-rich membrane regions due to electrostatic interactions promoting adhesion of cationic hIAPP peptides with anionic gangliosides.…”

Section: Iapp-membrane Interactionsmentioning

confidence: 99%

Amyloid-Mediated Mechanisms of Membrane Disruption

2021

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Protein aggregation and amyloid formation are pathogenic events underlying the development of an increasingly large number of human diseases named “proteinopathies”. Abnormal accumulation in affected tissues of amyloid β (Aβ) peptide, islet amyloid polypeptide (IAPP), and the prion protein, to mention a few, are involved in the occurrence of Alzheimer’s (AD), type 2 diabetes mellitus (T2DM) and prion diseases, respectively. Many reports suggest that the toxic properties of amyloid aggregates are correlated with their ability to damage cell membranes. However, the molecular mechanisms causing toxic amyloid/membrane interactions are still far to be completely elucidated. This review aims at describing the mutual relationships linking abnormal protein conformational transition and self-assembly into amyloid aggregates with membrane damage. A cross-correlated analysis of all these closely intertwined factors is thought to provide valuable insights for a comprehensive molecular description of amyloid diseases and, in turn, the design of effective therapies.

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