Probing the pressure–temperature stability of amyloid fibrils provides new insights into their molecular properties

Meersman, Filip; Dobson, Christopher M.

doi:10.1016/j.bbapap.2005.10.021

Cited by 155 publications

(143 citation statements)

References 86 publications

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“…Studies probing the stability of amyloid fibers suggest that water exclusion is part of the temporal transition transition process from the early stage of amorphous aggregation to that of fibrillation [36]. During the maturation phase, side chain packing and intramolecular hydrogen bond formation between beta-sheets are optimized [36]. Therefore, the packing of amyloid peptides in fibril strands reaches the optimum value while, water in the interior of the fibril strands vanishes.…”

Section: Discussionmentioning

confidence: 99%

“…Although initial studies of the amyloid structures suggested that the strands composing the fibrils are filled with water [31,32], recent data indicate that this is unlikely [33][34][35]. Studies probing the stability of amyloid fibers suggest that water exclusion is part of the temporal transition transition process from the early stage of amorphous aggregation to that of fibrillation [36]. During the maturation phase, side chain packing and intramolecular hydrogen bond formation between beta-sheets are optimized [36].…”

Section: Discussionmentioning

confidence: 99%

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Hydration Profiles of Amyloidogenic Molecular Structures

et al. 2008

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Hydration shells of normal proteins display regions of highly structured water as well as patches of less structured bulk-like water. Recent studies suggest that isomers with larger surface densities of patches of bulk-like water have an increased propensity to aggregate. These aggregates are toxic to the cellular environment. Hence, the early detection of these toxic deposits is of paramount medical importance. We show that various morphological states of association of such isomers can be differentiated from the normal protein background based on the characteristic partition between bulk, caged, and surface hydration water and the magnetic resonance (MR) signals of this water. We derive simple mathematical equations relating the compartmentalization of water to the local hydration fraction and the packing density of the newly formed molecular assemblies. Then, we employ these equations to predict the MR response of water constrained by protein aggregation. Our results indicate that single units and compact aggregates that contain no water between constituents induce a shift of the MR signal from normal protein background to values in the hyperintensity domain (bright spots), corresponding to bulk water. In contrast, large plaques that cage significant amounts of water between constituents are likely to generate MR responses in the hypointensity domain (dark spots), typical for strongly correlated water. The implication of these results is that amyloids can display both dark and bright spots when compared to the normal gray background tissue on MR images. In addition, our findings predict that the bright spots are more likely to correspond to amyloids in their early stage of development. The results help explain the MR contrast patterns of amyloids and suggest a new approach for identifying unusual protein aggregation related to disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hydration Profiles of Amyloidogenic Molecular Structures

et al. 2008

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“…Dissociation of amyloid fibrils can be triggered by the addition of highly concentrated chemical denaturants such as urea or guanidinium hydrochloride or of trifluoroethanol and the use of high temperature (30 -34). Although not as well studied, the application of elevated pressure has also been used to dissociate non-mature amyloid fibrils and proto-fibrils of several proteins (35)(36)(37)(38)(39)(40)(41)(42).…”

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confidence: 99%

Amyloid Features and Neuronal Toxicity of Mature Prion Fibrils Are Highly Sensitive to High Pressure

Moustaine

Perrier

et al. 2011

Journal of Biological Chemistry

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Prion proteins (PrP) can aggregate into toxic and possibly infectious amyloid fibrils. This particular macrostructure confers on them an extreme and still unexplained stability. To provide mechanistic insights into this self-assembly process, we used high pressure as a thermodynamic tool for perturbing the structure of mature amyloid fibrils that were prepared from recombinant full-length mouse PrP. Application of high pressure led to irreversible loss of several specific amyloid features, such as thioflavin T and 8-anilino-1-naphthalene sulfonate binding, alteration of the characteristic proteinase K digestion pattern, and a significant decrease in the ␤-sheet structure and cytotoxicity of amyloid fibrils. Partial disaggregation of the mature fibrils into monomeric soluble PrP was observed. The remaining amyloid fibrils underwent a change in secondary structure that led to morphologically different fibrils composed of a reduced number of proto-filaments. The kinetics of these reactions was studied by recording the pressure-induced dissociation of thioflavin T from the amyloid fibrils. Analysis of the pressure and temperature dependence of the relaxation rates revealed partly unstructured and hydrated kinetic transition states and highlighted the importance of collapsing and hydrating inter-and intramolecular cavities to overcome the high free energy barrier that stabilizes amyloid fibrils.Amyloid fibrils are filamentous polypeptide aggregates that are associated with devastating disorders such as Alzheimer and Parkinson diseases, type II diabetes, and prion (proteinaceous infectious particle) diseases, including Creutzfeldt-Jakob and mad cow disease (1, 2). There is increasing evidence that under appropriate conditions the amyloid state is accessible also to many other proteins that are not related to diseases, suggesting that the amyloid state is a generic structural feature, which might be adopted by any polypeptide chain (3-6).The development of in vitro model systems together with various biophysical and biochemical techniques (7-9) has improved the knowledge on the physicochemical basis of amyloid formation as well as on their structural and biochemical properties. It is now well recognized that a common property of amyloid fibrils is the extensive stacking of intermolecular ␤-strands that are arranged perpendicularly to the fibril axis and stabilized by a dense network of non-covalent interactions (10 -13). These fibrils consist of a variable number and arrangement of thin assemblies called proto-filaments that give rise to different fibril morphologies of diameters between 5 and 30 nanometers, both in in vitro preparations or in tissues (14 -22). Fibrils and their precursors are generally cytotoxic (23, 24) and are, thus, thought to be responsible for the neurodegeneration that is associated with many amyloid diseases.Yet the fundamental parameters that govern the protein aggregation process and dictate fibril stability/clearance are not well known. As the study of protein folding has been greatly advanc...

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“…74,75 In a similar way, the pressure is kept constant at 1 bar by the Parrinello−Rahman algorithm 76 (τ = 1 fs). The temperature of 310 K is chosen as a compromise between preserving the experimentally observed stability of the amyloid fibrils 77 and the desire to enhance sampling by raising temperature. 78,79 The solvated start configuration is first energy minimized using the steepest descent method, followed by conjugate gradient.…”

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confidence: 99%

In Silico Cross Seeding of Aβ and Amylin Fibril-like Oligomers

Berhanu

Yaşar

Hansmann

2013

ACS Chem. Neurosci.

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Recent epidemiological data have shown that patients suffering from Type 2 Diabetes Mellitus have an increased risk to develop Alzheimer's disease and vice versa. A possible explanation is the cross-sequence interaction between Aβ and amylin. Because the resulting amyloid oligomers are difficult to probe in experiments, we investigate stability and conformational changes of Aβ−amylin heteroassemblies through molecular dynamics simulations. We find that Aβ is a good template for the growth of amylin and vice versa. We see water molecules permeate the β-strand−turn−β-strand motif pore of the oligomers, supporting a commonly accepted mechanism for toxicity of β-rich amyloid oligomers. Aiming for a better understanding of the physical mechanisms of cross-seeding and cell toxicity of amylin and Aβ aggregates, our simulations also allow us to identify targets for the rational design of inhibitors against toxic fibril-like oligomers of Aβ and amylin oligomers.

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Probing the pressure–temperature stability of amyloid fibrils provides new insights into their molecular properties

Cited by 155 publications

References 86 publications

Hydration Profiles of Amyloidogenic Molecular Structures

Hydration Profiles of Amyloidogenic Molecular Structures

Amyloid Features and Neuronal Toxicity of Mature Prion Fibrils Are Highly Sensitive to High Pressure

In Silico Cross Seeding of Aβ and Amylin Fibril-like Oligomers

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