Amyloid fibril from the antimicrobial peptide uperin 3.5
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ABSTRACT:
SUBMITTER: Robert Bücker
PROVIDER: EMPIAR-11278 | biostudies-other |
REPOSITORIES: biostudies-other
Publications
The Cryo-EM structures of two amphibian antimicrobial cross-β amyloid fibrils.
Bücker Robert R Seuring Carolin C Cazey Cornelia C Veith Katharina K García-Alai Maria M Grünewald Kay K Landau Meytal M
Nature communications 20220727 1
The amyloid-antimicrobial link hypothesis is based on antimicrobial properties found in human amyloids involved in neurodegenerative and systemic diseases, along with amyloidal structural properties found in antimicrobial peptides (AMPs). Supporting this hypothesis, we here determined the fibril structure of two AMPs from amphibians, uperin 3.5 and aurein 3.3, by cryogenic electron microscopy (cryo-EM), revealing amyloid cross-β fibrils of mated β-sheets at atomic resolution. Uperin 3.5 formed a ...[more]
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Project description: Not available
| EMPIAR-11270 | biostudies-other
Project description: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.
| S-EPMC7826344 | biostudies-literature
Project description:Amyloid fibrils are found in systemic amyloidosis diseases such as Alzheimer's disease, Parkinson's disease, and type II diabetes. Currently, these diseases are diagnosed by observation of fibrils or plaques, which is an ineffective method for early diagnosis and treatment of disease. The goal of this study was to develop a simple and quick method to predict the possibility and speed of fibril formation before its occurrence. Oligomers generated from seven representative peptide segments were first isolated and detected by ion-mobility mass spectrometry (IM-MS). Then, their assemblies were disrupted using formic acid (FA). Interestingly, oligomers that showed small ion intensity changes upon FA addition had rapid fibril formation. By contrast, oligomers that had large ion intensity changes generated fibrils slowly. Two control peptides (aggregation/no fibrils and no aggregation/no fibrils) did not show changes in their ion intensities, which confirmed the ability of this method to predict amyloid formation. In summary, the developed method correlated MS intensity ratio changes of peptide oligomers on FA addition with their amyloid propensities. This method will be useful for monitoring peptide/protein aggregation behavior and essential for their mechanism studies.
| S-EPMC7193079 | biostudies-literature
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| S-EPMC5883547 | biostudies-literature
Project description:A macrocyclic ?-sheet peptide containing two nonapeptide segments based on A?(15-23) (QKLVFFAED) forms fibril-like assemblies of oligomers in the solid state. The X-ray crystallographic structure of macrocyclic ?-sheet peptide 3 was determined at 1.75 Å resolution. The macrocycle forms hydrogen-bonded dimers, which further assemble along the fibril axis in a fashion resembling a herringbone pattern. The extended ?-sheet comprising the dimers is laminated against a second layer of dimers through hydrophobic interactions to form a fibril-like assembly that runs the length of the crystal lattice. The second layer is offset by one monomer subunit, so that the fibril-like assembly is composed of partially overlapping dimers, rather than discrete tetramers. In aqueous solution, macrocyclic ?-sheet 3 and homologues 4 and 5 form discrete tetramers, rather than extended fibril-like assemblies. The fibril-like assemblies of oligomers formed in the solid state by macrocyclic ?-sheet 3 represent a new mode of supramolecular assembly not previously observed for the amyloidogenic central region of A?. The structures observed at atomic resolution for this peptide model system may offer insights into the structures of oligomers and oligomer assemblies formed by full-length A? and may provide a window into the propagation and replication of amyloid oligomers.
| S-EPMC4183627 | biostudies-literature
Project description:The molecular conformation of peptide fragment 105-115 of transthyretin, TTR(105-115), previously shown to form amyloid fibrils in vitro, has been determined by magic-angle spinning solid-state NMR spectroscopy. 13C and 15N linewidth measurements indicate that TTR(105-115) forms a highly ordered structure with each amino acid in a unique environment. 2D 13C-13C and 15N-13C-13C chemical shift correlation experiments, performed on three fibril samples uniformly 13C,15N-labeled in consecutive stretches of 4 aa, allowed the complete sequence-specific backbone and side-chain 13C and 15N resonance assignments to be obtained for residues 105-114. Analysis of the 15N, 13CO, 13Calpha, and 13Cbeta chemical shifts allowed quantitative predictions to be made for the backbone torsion angles phi and psi. Furthermore, four backbone 13C-15N distances were determined in two selectively 13C,15N-labeled fibril samples by using rotational-echo double-resonance NMR. The results show that TTR(105-115) adopts an extended beta-strand conformation that is similar to that found in the native protein except for substantial differences in the vicinity of the proline residue.
| S-EPMC139215 | biostudies-literature
Project description:Amyloid-β peptide (Aβ) aggregation is one of the hallmarks of Alzheimer's disease (AD). Mutations in Aβ are associated with early onset familial AD, and the Arctic mutant E22G (Aβarc) is an extremely aggregation-prone variant. Here, we show that BRICHOS, a natural anti-amyloid chaperone domain, from Bri2 efficiently inhibits aggregation of Aβarc by mainly interfering with secondary nucleation. This is qualitatively different from the microscopic inhibition mechanism for the wild-type Aβ, against which Bri2 BRICHOS has a major effect on both secondary nucleation and fibril end elongation. The monomeric Aβ42arc peptide aggregates into amyloid fibrils significantly faster than wild-type Aβ (Aβ42wt), as monitored by thioflavin T (ThT) binding, but the final ThT intensity was strikingly lower for Aβ42arc compared to Aβ42wt fibrils. The Aβ42arc peptide formed large aggregates, single-filament fibrils, and multiple-filament fibrils without obvious twists, while Aβ42wt fibrils displayed a polymorphic pattern with typical twisted fibril architecture. Recombinant human Bri2 BRICHOS binds to the Aβ42arc fibril surface and interferes with the macroscopic fibril arrangement by promoting single-filament fibril formation. This study provides mechanistic insights on how BRICHOS efficiently affects the aggressive Aβ42arc aggregation, resulting in both delayed fibril formation kinetics and altered fibril structure.
| S-EPMC9396614 | biostudies-literature
Project description:Metal ions have emerged to play a key role in the aggregation process of amyloid β (Aβ) peptide that is closely related to the pathogenesis of Alzheimer's disease. A detailed understanding of the underlying mechanistic process of peptide-metal interactions, however, has been challenging to obtain. By applying a combination of NMR relaxation dispersion and fluorescence kinetics methods we have investigated quantitatively the thermodynamic Aβ-Zn(2+) binding features as well as how Zn(2+) modulates the nucleation mechanism of the aggregation process. Our results show that, under near-physiological conditions, substoichiometric amounts of Zn(2+) effectively retard the generation of amyloid fibrils. A global kinetic profile analysis reveals that in the absence of zinc Aβ40 aggregation is driven by a monomer-dependent secondary nucleation process in addition to fibril-end elongation. In the presence of Zn(2+), the elongation rate is reduced, resulting in reduction of the aggregation rate, but not a complete inhibition of amyloid formation. We show that Zn(2+) transiently binds to residues in the N terminus of the monomeric peptide. A thermodynamic analysis supports a model where the N terminus is folded around the Zn(2+) ion, forming a marginally stable, short-lived folded Aβ40 species. This conformation is highly dynamic and only a few percent of the peptide molecules adopt this structure at any given time point. Our findings suggest that the folded Aβ40-Zn(2+) complex modulates the fibril ends, where elongation takes place, which efficiently retards fibril formation. In this conceptual framework we propose that zinc adopts the role of a minimal antiaggregation chaperone for Aβ40.
| S-EPMC4418866 | biostudies-literature
Project description:Using the peptide hormone glucagon and Abeta(1-40) as model systems, we have sought to elucidate the mechanisms by which fibrils grow and multiply. We here present real-time observations of growing fibrils at a single-fibril level. Growing from preformed seeds, glucagon fibrils were able to generate new fibril ends by continuously branching into new fibrils. To our knowledge, this is the first time amyloid fibril branching has been observed in real-time. Glucagon fibrils formed by branching always grew in the forward direction of the parent fibril with a preferred angle of 35-40 degrees . Furthermore, branching never occurred at the tip of the parent fibril. In contrast, in a previous study by some of us, Abeta(1-40) fibrils grew exclusively by elongation of preformed seeds. Fibrillation kinetics in bulk solution were characterized by light scattering. A growth process with branching, or other processes that generate new ends from existing fibrils, should theoretically give rise to different fibrillation kinetics than growth without such a process. We show that the effect of adding seeds should be particularly different in the two cases. Our light-scattering data on glucagon and Abeta(1-40) confirm this theoretical prediction, demonstrating the central role of fibril-dependent nucleation in amyloid fibril growth.
| S-EPMC2717229 | biostudies-literature
Project description:Using replica exchange molecular dynamics, we study the effect of Asp23Tyr mutation on Abeta(10-40) fibril growth. The effect of this mutation is revealed through the computation of free energy landscapes, the distributions of peptide-fibril interactions, and by comparison with the wild-type Abeta(10-40) peptide. Asp23Tyr mutation has a relatively minor influence on the docking of Abeta peptides to the fibril. However, it has a strong impact on the locking stage due to profound stabilization of the parallel in-registry beta-sheets formed by the peptides on the fibril edge. The enhanced stability of parallel beta-sheets results from the deletion of side chain interactions formed by Asp23, which are incompatible with the fibril-like conformers. Consequently, Asp23Tyr mutation is expected to promote fibril growth. We argue that strong off-registry side chain interactions may slow down fibril assembly as it occurs for the wild-type Abeta peptide. The analysis of experimental data offers support to our in silico conclusions.
| S-EPMC2765228 | biostudies-literature