V N Uversky

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..The correlation between fibrillation and the partially unfolded monomer indicates that the latter is a critical amyloidogenic intermediate in insulin fibrillation...

..Many well represented domains recognize and bind to primary sequences less than 10 amino acids in length called Short Linear Motifs (SLiMs)...

..Thus, the competence of a protein to form equilibrium intermediate(s) may be determined by the bulk content of hydrophobic and charged amino acid residues rather than by the positioning of amino acids within the sequence...

..This choice is dictated by the peculiarities of amino acid sequence and/or by the pressure of environmental factors. The aim of the present review is to outline some interesting features of these three routes...

..The peculiarities of this astonishing conformational behavior are analyzed to shed light on structural plasticity of this protein-chameleon...

..The results show that the spectral properties of the insulins reflect their state of association, and can be used to predict their oligomeric state...

..Zinc-loaded protein remains effectively unfolded. Possible implications of these findings to the functioning of PDEgamma are discussed...

..The latter conformation was significantly helical and probably represents the physiologically folded form of the protein...

..Finally, in comparison with the globular proteins, natively unfolded polypeptides possess 'turn out' responses to changes in the environment, as their structural complexities increase at high temperature or at extreme pH...

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..This inhibitory effect was eliminated at low pH. The addition of oxidized alpha-synuclein to the unoxidized form led to a substantial inhibition of alpha-synuclein fibrillation...

..Our results suggest that the major factor responsible for the accelerated fibrillation under crowded conditions is the excluded volume...

..This correlation provides experimental support for the hypothesis that hydrophobic collapse occurs simultaneously with formation of secondary structure in the early stages of the protein folding...

..In this respect, the Protein Quartet model, with function arising from four specific conformations (ordered forms, molten globules, premolten globules, and random coils) and transitions between any two of the states, is discussed...

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..It is possible that these structural changes may be important for the function of this protein...

..Suggested neurotoxicity mechanisms of these chemicals are considered, and the major lessons learned from the analysis of pesticide-induced PD models are discussed...

..The inherent flexibility of such an intermediate is essential in allowing the conformational rearrangements necessary to form the core cross-beta structure of the amyloid fibril...

..It is possible that such conformational changes may be associated with the protein function...

..A kinetic model, involving the association of monomeric partially folded intermediates, whose concentration is stimulated by the air-water interface, leading to formation of the critical nucleus and thence fibrils, is proposed...

..These observations suggest one possible underlying molecular basis for Parkinson's disease...

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..pestis Yop virulon. Thus, these results help to explain the importance of Caf1 in the interaction of Y. pestis with the host immune system...

..This means that the structure of the artificial protein albebetin can be improved by a simple procedure of octapeptide grafting to its N-terminus...

..This increased propensity of these mutants to aggregate, relative to wild-type alpha-synuclein, would account for the correlation of these mutations with Parkinson's disease...

..The results indicate that low concentrations of some metals can directly induce alpha-synuclein fibril formation...

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..This means that the quaternary structure, being an important stabilizing factor, does not represent the only circumstance dictating the dramatic variations between fluorescent proteins in their conformational stabilities...

..A model for insulin fibril formation is proposed in which the formation of a partially folded intermediate is the precursor for associated species on the pathway to fibril formation...

..These data suggest that partially folded alpha-synuclein, which is unstable in the monomeric form, is stabilized by self-assembly and that these oligomers may evolve into the fibril nucleus...

..At least to some extent, these conformational effects mimic those observed in the presence of phospholipid vesicles, and can explain some of the observed effects of membranes on alpha-synuclein fibrillation...

..Thus, increasing concentrations of urea, by triggering dissociation of dimeric LEN, lead to increased rates of fibrillation...

..In contrast, processes of HSA denaturation and unfolding are completely reversible. Release of ligands from HSA results only in a small decrease in stability but not transformation into the molten globule state...

..Interaction of permuted protein with ligands leads to the structural adjustment and formation of active protein molecules...

..These findings indicate that a combination of oxidative stress and environmental metal pollution could play an important role in triggering the fibrillation of alpha-synuclein and thus possibly Parkinson's disease...

..Both have significantly non-native conformations, and indicate that fibrillation occurs from a beta-rich structure significantly distinct from the native fold...

..The presence of zinc was shown to overcome the Met oxidation-induced inhibition. Interestingly, substitution of Met by Leu led to increased propensity for aggregation (soluble oligomers) but slower formation of fibrils...

..Since there is some evidence that Lewy bodies may contain GAGs, these observations may be very relevant in the context of the etiology of Parkinson's disease...

..It activates the blast transformation reaction of thymocyte cells even more efficiently than human interferon at low concentrations...

..The results suggest that, in general, marginally stable globular proteins will be significantly stabilized by salts under conditions where they have a substantial net charge...

..The fact that Congo red binds to native, partially folded conformations and amyloid fibrils of several proteins shows that it must be used with caution as a diagnostic test for the presence of amyloid fibrils in vitro...

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..Possible implications of these findings to the functioning of recoverin are discussed...

..These new findings demonstrate the potential effect of environmental pollutants in generating an amyloidogenic, and potentially neurotoxic, conformation, in an otherwise benign protein...

..e., injections of the herbicide paraquat). These observations indicate that translocation into the nucleus and binding with histones represent potential mechanisms underlying alpha-synuclein pathophysiology...

..HCl increased the rate of fibrillation, although much less than NaCl. Different ions also differentially affected the rate of nucleation and the rate of fibril elongation...

..e., native protein molecule cannot be reconstituted from the ligand-free form of AFP by adding back ligands. A possible functional role of such a structural transformation is discussed...

..In addition, more globularity, as determined from Kratky plots of small-angle x-ray scattering data, was also noted in the associated states...

..This change is absent upon binding of NO, YC-1 or ODQ alone. Using this and previous data, we propose a working model for the mechanism of activation of sGC by NO and YC-1 and inhibition by ODQ...

..This suggests that association of a protein molecule in partially folded conformations can be an additional structure forming factor...

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..4 +/- 0.2 microM) leads only to a very moderate folding of this protein and CaD136 remains substantially unfolded within its tight complex with calmodulin. The biological significance of these observations is discussed...

..Pesticides and metals, which are linked to increased risk of Parkinson's disease by epidemiological studies, are shown to accelerate alpha-synuclein fibrillation under conditions of molecular crowding...

..Moderate concentrations of anions affected both the rates of nucleation and the elongation of alpha-synuclein fibrillation, primarily via their effect on the interaction of the protein with water...

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..This effect was rather similar to that of the monomeric protein, suggesting that targeted stabilization of certain alpha-synuclein oligomers might offer a potential strategy for the development of novel Parkinson's disease therapies...

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..The specificity of such interaction is confirmed by the inhibition of IL-1alpha binding by Caf1. The Caf1 role in pneumonic plague pathogenesis is discussed...

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..We propose a model in which environmentalfactors in conjunction with genetic susceptibility may form the underlying molecular basis for idiopathic PD...

..We propose a model for the fibrillation of alpha-synuclein in which the first step is the conformational transformation of the natively unfolded protein into the aggregation-competent partially folded intermediate...

..These results reaffirm that alanine substitution in site specific mutagenesis is not always a prudent choice. Substitutions must be conservative with only minimal changes in functional groups and side-chain volume...

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..It is shown that association of non-native conformations of the protein molecule can be an additional structuring factor. The corresponding folding schemes and phase diagrams are suggested...

..Thus, membranes may have significant effects on light-chain fibrillation and may contribute to the site selectivity observed in AL amyloidosis...

..These data taken together suggest that besides established earlier crucial catalytic role, Arg96 is important for the overall folding and conformational stability of GFP...

..We used two hierarchical neural network methods to predict the secondary structure of sGC and found it to be consistent with the observed CD spectrum of sGC...

..The addition of nitrated alpha-synuclein inhibited fibrillation of non-modified alpha-synuclein at neutral pH. Potential implications of these findings to the etiology of Parkinson's disease are discussed...

..The native rigid tertiary structure of PA is attained upon association of one (alpha-PA) or two (beta-PA) calcium ions per protein molecule, as follows from calorimetric and calcium titration data...

..The effect observed has to be taken into account in any UV-region spectral studies of alpha-lactalbumin...

..Finally, oxidation of methionines by H2O2 greatly inhibited alpha-Syn fibrillation in vitro, leading to the formation of relatively stable oligomers, which are not toxic to dopaminergic and GABAergic neurons...

..The flavonoids inhibiting alpha-synuclein fibrillation and stabilizing the protein monomeric conformation can serve as a model for the development of therapeutic drugs in combating Parkinson's disease...

..Such strong interactions without major structural consequences are highly unusual, and AFP may therefore be the first characterized representative of a new class of ligand-binding proteins...

..The lack of fibrils formed by beta-synuclein is most readily explained by the absence of a stretch of hydrophobic residues from the middle region of the protein. A model for the inhibition is proposed...

..These observations suggest that nitration of soluble alpha-synuclein may be a protective factor in PD, rather than a causative one...

..The Ca(2+)/Mg(2+) selectivity of Mg(2+)-site of EQL is below an order of magnitude. EQL exhibits a distinct Mg(2+)-specific site, probably arising as an adaptation to the extracellular environment...

..This work also demonstrates some novel NMR-based methodological approaches that provide useful information on protein self-association...

..A model of CK unfolding, which takes into account both structural perturbations and association of partially folded intermediates has been elaborated...

..The results illustrate the potential critical role of electrostatic interactions in protein aggregation, and the potential role of naturally occurring polycations in modulating alpha-synuclein aggregation...

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..This information can be used to understand the molecular mechanism of the nicotine and hydroquinone action to develop therapeutic solutions for PD...

..The data indicate that alpha-lactalbumin can be used as a basis for the design of antitumor agents, acting through disorganization of chromatin structure due to interaction between alpha-LA and histone proteins...

..A close structural similarity (including tendency for association) is shown between this intermediate and the least ordered A1-form, induced in the acid-unfolded nuclease by moderate sulfate or chloride concentrations...

..Ligand-free forms of protein are classified from the viewpoint of structural property changes of a protein molecule...

..The methionine-oxidized LEN preferred to form amorphous aggregates instead of fibrils. The results indicated that the LEN oxidation may play an important role in amorphous deposition of the protein, but not in its fibrillation...

..The Ca2+ modulated susceptibility of the recoverin thiol to reversible oxidation may be of potential importance for functioning of recoverin in photoreceptor cells...

..9 for both the alpha-helix and the beta-structure. Thus, the secondary structure of proteins in the molten globule state is close to that in the native state...

..IL-4delta2 interacts specifically with the alpha chain of IL-4R and competes effectively with IL-4 for the common binding sites. Thus, IL-4delta2 may act as a regulator of the cytokine net, being the natural antagonist of IL-4...

..Advantages and disadvantages of the technique suggested are also discussed...

..The requirement for efficient conversion of alpha-lactalbumin to the LAMPA state is a poly-Lys(Arg) chain consisting of several tens of amino acid residues...

..Furthermore, based on the EPR studies of model peptides and Beta-synuclein, we concluded that the suspected His residue did not appear to participate in strong Cu21 binding...

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..Composition Profiler is a web-based tool for semi-automatic discovery of enrichment or depletion of amino acids, either individually or grouped by their physico-chemical or structural properties...

..The results from genome-wide predictions of intrinsic disorder and the results from other bioinformatics studies of intrinsic disorder are demanding attention for these proteins...

..Furthermore the local flexibility in protein molecules appears to be dependent on the molecular confinement and is essentially larger in extracellular proteins...

..Therefore, DsRed can be used as a genetic reporter and advanced population marker with a significantly extended intracellular lifespan...

..Maximal populations of these intermediates are shifted toward higher GdmCl concentrations in the case of the adenylated ligase. These data provide further insights into the properties of partially folded intermediates...

..Finally, guanidine hydrochloride-induced unfolding of NAD(+)-dependent DNA ligases is shown to be a complex process that involves accumulation of at least two equilibrium intermediates, the molten globule and its precursor...

..Indeed, a vast majority of protein deposits in amyloid diseases are given by protein fragments derived from larger protein precursors...