Structural models of amyloid-like fibrils.
ABSTRACT Amyloid fibrils are elongated, insoluble protein aggregates deposited in vivo in amyloid diseases, and amyloid-like fibrils are formed in vitro from soluble proteins. Both of these groups of fibrils, despite differences in the sequence and native structure of their component proteins, share common properties, including their core structure. Multiple models have been proposed for the common core structure, but in most cases, atomic-level structural details have yet to be determined. Here we review several structural models proposed for amyloid and amyloid-like fibrils and relate features of these models to the common fibril properties. We divide models into three classes: Refolding, Gain-of-Interaction, and Natively Disordered. The Refolding models propose structurally distinct native and fibrillar states and suggest that backbone interactions drive fibril formation. In contrast, the Gain-of-Interaction models propose a largely native-like structure for the protein in the fibril and highlight the importance of specific sequences in fibril formation. The Natively Disordered models have aspects in common with both Refolding and Gain-of-Interaction models. While each class of model suggests explanations for some of the common fibril properties, and some models, such as Gain-of-Interaction models with a cross-beta spine, fit a wider range of properties than others, no one class provides a complete explanation for all amyloid fibril behavior.
Article: Repeat or not repeat?--Statistical validation of tandem repeat prediction in genomic sequences.[show abstract] [hide abstract]
ABSTRACT: Tandem repeats (TRs) represent one of the most prevalent features of genomic sequences. Due to their abundance and functional significance, a plethora of detection tools has been devised over the last two decades. Despite the longstanding interest, TR detection is still not resolved. Our large-scale tests reveal that current detectors produce different, often nonoverlapping inferences, reflecting characteristics of the underlying algorithms rather than the true distribution of TRs in genomic data. Our simulations show that the power of detecting TRs depends on the degree of their divergence, and repeat characteristics such as the length of the minimal repeat unit and their number in tandem. To reconcile the diverse predictions of current algorithms, we propose and evaluate several statistical criteria for measuring the quality of predicted repeat units. In particular, we propose a model-based phylogenetic classifier, entailing a maximum-likelihood estimation of the repeat divergence. Applied in conjunction with the state of the art detectors, our statistical classification scheme for inferred repeats allows to filter out false-positive predictions. Since different algorithms appear to specialize at predicting TRs with certain properties, we advise applying multiple detectors with subsequent filtering to obtain the most complete set of genuine repeats.Nucleic Acids Research 08/2012; · 8.03 Impact Factor
Article: Physiological Temperature Has a Crucial Role in Amyloid Beta in the Absence and Presence of Hydrophobic and Hydrophilic Nanoparticles[show abstract] [hide abstract]
ABSTRACT: Amyloid beta fibrillation can lead to major disorder of neurons pro-cesses and is associated with several neuronal diseases (e.g., Alzheimer's disease). We report here an importance of slight temperature changes, in the physiological range (35−42 °C), on the amyloid fibrillation process in the presence and absence of hydrophilic (silica) and hydrophobic (polystyrene) nanoparticles (NPs). The results highlight the fact that slight increases in temperature can induce inhibitory and acceleratory effects of hydrophobic and hydrophilic NPs on the fibrillation process, respectively. Using further in vivo considerations, the outcomes of this study can be used for considerable modifications on the current diagnosis and treatment approaches in amyloid-involved diseases. T he misfolding of amyloid proteins (e.g., amyloid beta (Aβ) peptide, 1−4 prion protein, 5 α-synuclein, 6 polyglutamine, 7 glucagon, 8 and β2-microglobulin 9,10) followed by their fibrilla-tion is the hallmark of over 40 human diseases, ranging from neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, Creutzfeld−Jakob disease, and Gerstmann−Strä ussler− Scheinker syndrome) to non-neuropathic disorders (e.g., amyloid heart disease, rheumatoid arthritis, and type II diabetes). 11,12 Among various amyloidogenic proteins, Aβ peptides are widely used as model proteins to investigate the effect of NPs on fibrillo-genesis. 13 Monomeric Aβ is actually soluble in a physiological condition and has shown to be unstructured; 14 however, the fibrillar form has a characteristic cross-β structure with stacking of β strands perpendicular to the long axis of the fiber. 15−17 It is well recognized that nanoparticles (NPs) have significant effect on the fibrillation process. 18−20 Interestingly, it was very recently found that graphene oxide sheets (GO) with a protein corona (protein/biomolecular coated GO in biological medium 21) can slow amyloid the fibrillation process. 22 Although there are few reports on the effect of temperature on the kinetics of amyloid fibrillation process, 23−26 a crucial effect of slight temperature changes (i.e., in the physiological range) on the amyloid fibrillation process in the presence of NPs has not been investigated. This point is very important for the in vivo NP application to humans, specifically for treatment of amyoloid proteins (e.g., Alzheimer's and Parkinson's disease). 27 The local temperature in different brain diseases/tumors for different individuals is in the range from 33.4 to 42.0 °C. 28−32 In normal body, the body tem-perature, during sleep, decreases and manual work leads to an increase of up to 2 °C. This means that the body temperature for healthy humans varies in the range from 35 to 39 °C and can find a maximum of 42 °C in the case of fever. 33 Although there are significant reports on the effects of various NPs on the amyloid fibrillation process, 34−38 as far as we know there is no report on the effects of slight temperature changes, in the phy-siological range, on the interactions between NPs and Aβ; thus,ACS Chemical Neuroscience 01/2013; · 3.68 Impact Factor