The redox environment triggers conformational changes and aggregation of hIAPP in Type II Diabetes

Camargo, Diana C. Rodriguez; Tripsianes, Konstantinos; Buday, Katalin; Frankó, András; Göbl, Christoph; Hartlmüller, Christoph; Sarkar, Riddhiman; Aichler, Michaela; Mettenleiter, Gabriele; Schulz, Michael; Böddrich, Annett; Erck, Christian; Martens, Henrik; Walch, Axel; Madl, Tobias; Wanker, Erich E.; Conrad, Marcus; Angelis, Martin Hrabé de; Reif, Bernd

doi:10.1038/srep44041

Cited by 81 publications

(97 citation statements)

References 55 publications

(64 reference statements)

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“…Recently, a novel ssNMR-based structure of the FUS amyloid core was reported, with similar structural features as noted above for other amyloid structures[101]. The peptide IAPP (also known as amylin) forms amyloid-like fibrils in type II diabetes, which have also been studied recently by ssNMR [102]. Human β-2-microglobulin (β2m) is involved in dialysis-related amyloidosis.…”

Section: Protein Aggregation In Human Diseasementioning

confidence: 78%

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

Wel

2017

Solid State Nuclear Magnetic Resonance

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The aggregation of proteins and peptides into a variety of insoluble, and often non-native, aggregated states plays a central role in many devastating diseases. Analogous processes undermine the efficacy of polypeptide-based biological pharmaceuticals, but are also being leveraged in the design of biologically inspired self-assembling materials. This Trends article surveys the essential contributions made by recent solid-state NMR (ssNMR) studies to our understanding of the structural features of polypeptide aggregates, and how such findings are informing our thinking about the molecular mechanisms of misfolding and aggregation. A central focus is on disease-related amyloid fibrils and oligomers involved in neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease. SSNMR-enabled structural and dynamics-based findings are surveyed, along with a number of resulting emerging themes that appear common to different amyloidogenic proteins, such as their compact alternating short-β-strand/β-arc amyloid core architecture. Concepts, methods, future prospects and challenges are discussed.

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Section: Protein Aggregation In Human Diseasementioning

confidence: 78%

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

Wel

2017

Solid State Nuclear Magnetic Resonance

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“…By reducing IAPP aggregation with detergent micelles, solution NMR studies have been used to study the structure of IAPP monomers. 137–139 It has been shown that SDS micelles stabilize IAPP in a highly helical form (Fig. 7b–d).…”

Section: Iapp and Type 2 Diabetesmentioning

confidence: 96%

Implications of peptide assemblies in amyloid diseases

et al. 2017

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Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology – much of which are poorly understood – these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer’s, Parkinson’s, type 2 diabetes and prions diseases. In addition, we discuss the toxicities of these amyloid proteins based on their self-assembly as well as their interactions with membranes, metal ions, small molecules and engineered nanoparticles. Through this presentation we show the remarkable similarities and differences in the structural transitions of the amyloid proteins through primary and secondary nucleation, the common evolution from disordered monomers to alpha-helices and then to β-sheets when the proteins encounter the cell membrane, and, the consensus (with a few exceptions) that off-pathway oligomers, rather than amyloid fibrils, are the toxic species regardless of the pathogenic protein sequence or physicochemical properties. In addition, we highlight the crucial role of molecular self-assembly in eliciting the biological and pathological consequences of the amyloid proteins within the context of their cellular environments and their spreading between cells and organs. Exploiting such structure-function-toxicity relationship may prove pivotal for the detection and mitigation of amyloid diseases.

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“…α -Helical intermediates have been detected during the lag phase for amyloid formation in amyloid- β , α -synuclein, and human islet amyloid polypeptide (hIAPP, also known as amylin), by CD, 27–29 NMR 29,30 EPR, 31 and fluorescence and neutron reflectometry 32 studies. There is evidence for antiparallel β -sheet structure in intermediates of amyloid- β , 33 α -synuclein, 34 and the SH3 domain.…”

Section: Introductionmentioning

confidence: 99%

A Free Energy Barrier Caused by the Refolding of an Oligomeric Intermediate Controls the Lag Time of Amyloid Formation by hIAPP

Serrano

Lomont

et al. 2017

J. Am. Chem. Soc.

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Transiently populated oligomers formed en route to amyloid fibrils may constitute the most toxic aggregates associated with many amyloid-associated diseases. Most nucleation theories used to describe amyloid aggregation predict low oligomer concentrations and do not take into account free energy costs that may be associated with structural rearrangements between the oligomer and fiber states. We have used isotope labeling and two-dimensional infrared spectroscopy to spectrally resolve an oligomeric intermediate during the aggregation of the human islet amyloid protein (hIAPP or amylin), the protein associated with type II diabetes. A structural rearrangement includes the F23G24A25I26L27 region of hIAPP, which starts from a random coil structure, evolves into ordered β-sheet oligomers containing at least 5 strands, and then partially disorders in the fibril structure. The supercritical concentration is measured to be between 150 and 250 μM, which is the thermodynamic parameter that sets the free energy of the oligomers. A 3-state kinetic model fits the experimental data, but only if it includes a concentration independent free energy barrier >3 kcal/mol that represents the free energy cost of refolding the oligomeric intermediate into the structure of the amyloid fibril; i.e., “oligomer activation” is required. The barrier creates a transition state in the free energy landscape that slows fibril formation and creates a stable population of oligomers during the lag phase, even at concentrations below the supercritical concentration. Largely missing in current kinetic models is a link between structure and kinetics. Our experiments and modeling provide evidence that protein structural rearrangements during aggregation impact the populations and kinetics of toxic oligomeric species.

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The redox environment triggers conformational changes and aggregation of hIAPP in Type II Diabetes

Cited by 81 publications

References 55 publications

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

Implications of peptide assemblies in amyloid diseases

A Free Energy Barrier Caused by the Refolding of an Oligomeric Intermediate Controls the Lag Time of Amyloid Formation by hIAPP

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