55 research outputs found
Alzheimer's Aβ Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu2+ Coordination
coordination of various Aβ peptides has been widely studied. A number of disease-associated modifications involving the first 3 residues are known, including isomerisation, mutation, truncation and cyclisation, but are yet to be characterised in detail. In particular, Aβ in plaques contain a significant amount of truncated pyroglutamate species, which appear to correlate with disease progression. coordination modes between pH 6–9 with nominally the same first coordination sphere, but with a dramatically different pH dependence arising from differences in H-bonding interactions at the N-terminus. coordination of Aβ, which may be critical for alterations in aggregation propensity, redox-activity, resistance to degradation and the generation of the Aβ3–× (× = 40/42) precursor of disease-associated Aβ3[pE]–x species
Cu(II) mediates kinetically distinct, non-amyloidogenic aggregation of amyloid-β peptides
Cu(II) ions are implicated in the pathogenesis of Alzheimer disease by influencing the aggregation of the amyloid-β (Aβ) peptide. Elucidating the underlying Cu(II)-induced Aβ aggregation is paramount for understanding the role of Cu(II) in the pathology of Alzheimer disease. The aim of this study was to characterize the qualitative and quantitative influence of Cu(II) on the extracellular aggregation mechanism and aggregate morphology of Aβ(1–40) using spectroscopic, microelectrophoretic, mass spectrometric, and ultrastructural techniques. We found that the Cu(II):Aβ ratio in solution has a major influence on (i) the aggregation kinetics/mechanism of Aβ, because three different kinetic scenarios were observed depending on the Cu(II):Aβ ratio, (ii) the metal:peptide stoichiometry in the aggregates, which increased to 1.4 at supra-equimolar Cu(II):Aβ ratio; and (iii) the morphology of the aggregates, which shifted from fibrillar to non-fibrillar at increasing Cu(II):Aβ ratios. We observed dynamic morphological changes of the aggregates, and that the formation of spherical aggregates appeared to be a common morphological end point independent on the Cu(II) concentration. Experiments with Aβ(1–42) were compatible with the conclusions for Aβ(1–40) even though the low solubility of Aβ(1–42) precluded examination under the same conditions as for the Aβ(1–40). Experiments with Aβ(1–16) and Aβ(1–28) showed that other parts than the Cu(II)-binding His residues were important for Cu(II)-induced Aβ aggregation. Based on this study we propose three mechanistic models for the Cu(II)-induced aggregation of Aβ(1–40) depending on the Cu(II):Aβ ratio, and identify key reaction steps that may be feasible targets for preventing Cu(II)-associated aggregation or toxicity in Alzheimer disease
Analysis of the impact of sex and age on the variation in the prevalence of antinuclear autoantibodies in Polish population: a nationwide observational, cross-sectional study
The detection of antinuclear autoantibody (ANA) is dependent on many factors and varies between the populations. The aim of the study was first to assess the prevalence of ANA in the Polish adult population depending on age, sex and the cutoff threshold used for the results obtained. Second, we estimated the occurrence of individual types of ANA-staining patterns. We tested 1731 patient samples using commercially available IIFA using two cutoff thresholds of 1:100 and 1:160. We found ANA in 260 participants (15.0%), but the percentage of positive results strongly depended on the cutoff level. For a cutoff threshold 1:100, the positive population was 19.5% and for the 1:160 cutoff threshold, it was 11.7%. The most prevalent ANA-staining pattern was AC-2 Dense Fine speckled (50%), followed by AC-21 Reticular/AMA (14.38%) ANA more common in women (72%); 64% of ANA-positive patients were over 50 years of age. ANA prevalence in the Polish population is at a level observed in other highly developed countries and is more prevalent in women and elderly individuals. To reduce the number of positive results released, we suggest that Polish laboratories should set 1:160 as the cutoff threshold
Peptides as potential ligands binding transition metal ions
Peptides are crucial ligands for transition metal ions and form complexes with
them, that can have important biological activity. Many factors impact on the creation
of complexes such as: protection of amine group from N-terminal or carboxylate
group from C-terminals of the protein, the presence of noncoordinating and
coordinating side chains in the peptide sequence, the number of histidyl residues
and their location in the peptide chain. In complexes the metal ion can be bound
bound by various donor atoms from amino acids residues (e.g. nitrogen, oxygen or
sulphur). In general, the protection of N- or C-terminal groups influences the less
stable formation of complexes. Stable complexes are created, if the free amine group
from the N-terminal is involved in the coordination process. Peptides with noncoordinating
side chains include alanine or glycine. Glycine complexes are more stable
than these with alanine. Histidyl residue is the most effective amino acid residue
in binding metal ions. The amine group of the lysyl residue, thiol from cysteine
or carboxylate from aspartyl or glutamyl residues are also functional groups that
coordinate metal ions. The coordination process is initiated by a group that anchors
metal ion. A free amine group from N-terminus or imidazole nitrogen are the
best examples of anchor groups. The metal ions can also be bound through amide
nitrogens, after their forced deprotonation by the anchor group and formation of
chelate rings. Peptides containing two or more histidyl residues exhibit high structural
diversity in the complexes formation. In addition, these peptides can also form
macrochelates and polynuclear complexes. The location of amino acid residues in
the peptide chain (especially histydyl residue) also results in the thermodynamically
stable formation of complexes
Copper(II) and oxovanadium(IV) complexes of alpha-hydroxymethylserine
Potentiometric and spectroscopic measurements were used to characterize the binding ability of -hydroxy-methylserine (Hms) with copper(II) and oxovanadium(IV) ions. The ligand was found to be generally a more efficient chelating agent than serine. Both of the deprotonated hydroxyl groups of Hms can be involved in coordination to vanadyl ions, whereas copper(II) binds in the same way as with serine
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