On the structural definitions of amyloid fibrils and other polypeptide aggregates Cell

Leibniz-Institut für Altersforschung, Beutenbergstrasse 11, 07745, Jena, Germany.
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 09/2007; 64(16):2066-78. DOI: 10.1007/s00018-007-7110-2
Source: PubMed


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.

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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 [26] [27] [28]. 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 [9] [29] [30] [10] [11] [31]. "
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    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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    • "Amyloids are insoluble fibrous deposits, formed by misfolded protein or peptide segments, in pathological cases [33], [34]. A growing number of ‘conformational diseases’, called amyloidoses, have been associated with the formation of amyloids [35], [36]. "
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    ABSTRACT: Zona pellucida (ZP) is an extracellular matrix surrounding and protecting mammalian and fish oocytes, which is responsible for sperm binding. Mammalian ZP consists of three to four glycoproteins, called ZP1, ZP2, ZP3, ZP4. These proteins polymerize into long interconnected filaments, through a common structural unit, known as the ZP domain, which consists of two domains, ZP-N and ZP-C. ZP is related in function to silkmoth chorion and in an evolutionary fashion to the teleostean fish chorion, also fibrous structures protecting the oocyte and embryo, that both have been proven to be functional amyloids. Two peptides were predicted as 'aggregation-prone' by our prediction tool, AMYLPRED, from the sequence of the human ZP1-N domain. Here, we present results from transmission electron microscopy, X-ray diffraction, Congo red staining and attenuated total reflectance Fourier-transform infrared spectroscopy (ATR FT-IR), of two synthetic peptide-analogues of these predicted 'aggregation-prone' parts of the human ZP1-N domain, that we consider crucial for ZP protein polymerization, showing that they both self-assemble into amyloid-like fibrils. Based on our experimental data, we propose that human ZP (hZP) might be considered as a novel, putative, natural protective amyloid, in close analogy to silkmoth and teleostean fish chorions. Experiments are in progress to verify this proposal. We also attempt to provide insights into ZP formation, proposing a possible model for hZP1-N domain polymerization.
    PLoS ONE 09/2013; 8(9):e73258. DOI:10.1371/journal.pone.0073258 · 3.23 Impact Factor
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    • "Amyloid structures constitute a specific subset of insoluble fibrous protein aggregates. These structures arise by sequences that allow the formation of intermolecular beta-sheet arrangements and their packing in the highly stable three-dimensional structure of amyloid fibrils [2]–[4]. The biological properties of these cross-β fibrillar aggregates differ from those of amorphous aggregates. "
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    ABSTRACT: The purpose of this work was to construct a consensus prediction algorithm of 'aggregation-prone' peptides in globular proteins, combining existing tools. This allows comparison of the different algorithms and the production of more objective and accurate results. Eleven (11) individual methods are combined and produce AMYLPRED2, a publicly, freely available web tool to academic users (, for the consensus prediction of amyloidogenic determinants/'aggregation-prone' peptides in proteins, from sequence alone. The performance of AMYLPRED2 indicates that it functions better than individual aggregation-prediction algorithms, as perhaps expected. AMYLPRED2 is a useful tool for identifying amyloid-forming regions in proteins that are associated with several conformational diseases, called amyloidoses, such as Altzheimer's, Parkinson's, prion diseases and type II diabetes. It may also be useful for understanding the properties of protein folding and misfolding and for helping to the control of protein aggregation/solubility in biotechnology (recombinant proteins forming bacterial inclusion bodies) and biotherapeutics (monoclonal antibodies and biopharmaceutical proteins).
    PLoS ONE 01/2013; 8(1):e54175. DOI:10.1371/journal.pone.0054175 · 3.23 Impact Factor
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