On the structural definition of amyloid fibrils and other polypeptide aggregates
ABSTRACT Amyloid fibrils occur inside the human body, associated with ageing or a group of diseases that includes, amongst others, Alzheimer's disease, atherosclerosis and type II diabetes. Many natural polypeptide chains are able to form amyloid fibrils in vivo or in vitro, and this ability has been suggested to represent an inherent consequence of the chemical structure of the polypeptide chain. Recent literature has provided a wealth of information about the structure of aggregates, precipitates, amyloid fibrils and other types of fibrillar polypeptide assemblies. However, the biophysical meaning associated with these terms can differ considerably depending on the context of their usage. This overview presents a structural comparison of amyloid fibrils and other types of polypeptide assemblies and defines amyloid fibrils, based on structural considerations, as fibrillar polypeptide aggregates with a cross-beta conformation.
- SourceAvailable from: Dirk Matthes
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- "Hence, the elucidation of individual structural polymorphs on an atomic level is challenging and the conclusions drawn so far are still controversial   . Obtaining structural constraints for models of full-length amyloid peptides and proteins beyond the molecular level proves to be a major task and requires considerable effort in designing suitable experimental protocols and the use of state-of-the-art instrumentation      . "
ABSTRACT: Recently, several short peptides have been shown to self-assemble into amyloid fibrils with generic cross-β spines, so-called steric zippers, suggesting common underlying structural features and aggregation mechanisms. Understanding these mechanisms is a prerequisite for designing fibril-binding compounds and inhibitors of fibril formation. The hexapeptide VEALYL, corresponding to the residues B12-17 of full-length insulin, has been identified as one of these short segments. Here, we analyzed the structures of multiple, morphologically different (fibrillar, microcrystal-like, oligomeric) [13C,15N]VEALYL samples by solid-state nuclear magnetic resonance complemented with results from molecular dynamics simulations. By performing NHHC/CHHC experiments, we could determine that the β-strands within a given sheet of the amyloid-like fibrils formed by the insulin hexapeptide VEALYL are stacked in an antiparallel manner, whereas the sheet-to-sheet packing arrangement was found to be parallel. Experimentally observed secondary chemical shifts for all aggregate forms, as well as ∅ and ψ backbone torsion angles calculated with TALOS, are indicative of β-strand conformation, consistent with the published crystal structure (PDB ID: 2OMQ). Thus, we could demonstrate that the structural features of all the observed VEALYL aggregates are in agreement with the previously observed homosteric zipper spine packing in the crystalline state, suggesting that several distinct aggregate morphologies share the same molecular architecture.Journal of Molecular Biology 01/2014; 426(2):362–376. DOI:10.1016/j.jmb.2013.10.020 · 4.33 Impact Factor
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- "Where fibrils are comprised of β-sheets running perpendicular to the fibril axis, they are termed 'amyloid' or amyloid-like'. 'Amyloid' derives from the association with amyloidosis diseases, such as Alzheimer's and Parkinson's disease, and 'amyloid-like' refers to structurally similar fibrils formed in vitro (Fändrich, 2007). "
ABSTRACT: We investigated the effects of pH (1.6–2.4), NaCl and CaCl2 (0–100 mm) on the kinetics of β-lactoglobulin fibril formation during heating at 80 °C. The morphology of fibrils was also examined. At pH 1.8–2.4 fibril formation occurred slightly faster with decreasing pH. At pH 1.6 fibril formation during the growth phase occurred much faster than at any other pH. Fibril morphology was unchanged between pH 1.6 and pH 2.0. Addition of NaCl or CaCl2 accelerated fibril formation during the growth phase, and CaCl2 shortened the lag phase as well. Worm-like fibrils were seen at ≥60 mm NaCl or ≥33 mm CaCl2, and these had a persistence length which was much shorter than the long semi-flexible fibrils formed without salts. The efficiency of fibril formation can be substantially enhanced by varying pH and salt concentration.
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ABSTRACT: A number of neurodegenerative disorders have recently been coalesced into a group of proteinopathies because of the similarity of molecular mechanisms underlying their pathogenesis. A key step in the development of proteinopathies is a structural change that triggers aggregation of proteins, which are intrinsically prone to form aggregates due to their physical and chemical properties. Present review is devoted to the recent progress in the field of proteinopathies with specific focus on properties of aggregate-prone proteins, main stages of the development of molecular pathology and the role of cellular clearance systems in progression of neurodegeneration. Recent modifications in the nomenclature of neurodegenerative diseases will also be addressed.Molekuliarnaia biologiia 05/2012; 46(3):402-15. DOI:10.1134/S0026893312020161