Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 comprised antiparallel and parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 demonstrated chameleon properties of a secondary structure switch, forming mostly cross-β fibrils in the absence of lipids. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.
Extensive work has been invested in the design of bio-inspired peptide emulsifiers. Yet, none of the formulated surfactants were based on the utilization of the robust conformation and self-assembly tendencies presented by the hydrophobins, which exhibited highest surface activity among all known proteins. Here we show that a minimalist design scheme could be employed to fabricate rigid helical peptides to mimic the rigid conformation and the helical amphipathic organization. These designer building blocks, containing natural non-coded α-aminoisobutyric acid (Aib), form superhelical assemblies as confirmed by crystallography and microscopy. The peptide sequence is amenable to structural modularity and provides the highest stable emulsions reported so far for peptide and protein emulsifiers. Moreover, we establish the ability of short peptides to perform the dual functions of emulsifiers and thickeners, a feature that typically requires synergistic effects of surfactants and polysaccharides. This work provides a different paradigm for the molecular engineering of bioemulsifiers.
Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic-resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 were comprised of parallel and anti-parallel helical sheets, respectively, recapitulating properties of β-sheets.Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. Uperin 3.5 demonstrated chameleon properties, with a secondary structure switch to cross-β fibrils with reduced antibacterial activity in the absence of lipids or after heat shock. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.
Parkinson’s
disease is characterized by the self-assembly
of α-synuclein (AS), in which its aggregates accumulate in the
substantia nigra. The molecular mechanisms of the self-assembly of
AS are challenging because AS is a relatively large intrinsically
disordered protein, consisting of 140 residues. It is known that the
N-termini of AS contribute to the toxicity of the proteins; therefore,
it is important to investigate the self-assembly structure of the
N-termini on AS as well. There have been extensive efforts to investigate
the structural fibrils of AS(1–140), which have shown that
the N-termini are disordered and do not participate in the fibrillary
structure. This study illustrates for the first time that the N-termini
of AS play a crucial role in the self-assembly of AS. This study reveals
a new structure of AS(1–140) fibrils, in which the N-termini
are essential parts of the cross-β structure of the fibrillary
structure. This study suggests that there are polymorphic states of
the self-assembled AS(1–140). While the polymorphic states
of the N-termini do not participate in the fibrillary structure and
fluctuate, our predicted new fibrillary structure of the N-termini
not only participates in the fibrillary structure but also stabilizes
the fibrillary structure.
The effect of Cu2+ on α-synuclein (AS) aggregation is important because
clinical studies of patients with Parkinson’s disease have
shown elevated levels of Cu2+ in the cerebrospinal fluid.
So far, the molecular architectures of Cu2+–AS fibril
complexes at atomic resolution are unknown. The current work identifies
for the first time that His50 cannot bind Cu2+ ions in
mature fibrils. Moreover, it shows hopping of Cu2+ ions
between residues in AS fibrils and changes in the Cu2+ coordination
mode in Cu2+ ions that bind in the termini of AS. The current
study combines extensive experimental techniques, density functional
theory calculations, and computational modeling tools to provide a
complete description of the Cu2+ binding site in AS fibrils.
Our findings illustrate for the first time the specific interactions
between Cu2+ ions and AS fibrils, suggesting a new mechanistic
perspective on the effect of Cu2+ ions on AS aggregation.
Reactive aldehydes generated in cells and tissues are associated with adverse physiological effects. Dihydroxyphenylacetaldehyde (DOPAL), the biogenic aldehyde enzymatically produced from dopamine, is cytotoxic, generates reactive oxygen species, and triggers...
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