Conversion of α-Helical Proteins into an Alternative β-Amyloid Fibril Conformation

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.

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Molecular structure of an N-terminal phosphorylated β-amyloid fibril

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1818530116 ◽

2019 ◽

Vol 116 (23) ◽

pp. 11253-11258 ◽

Cited By ~ 11

Author(s):

Zhi-Wen Hu ◽

Liliya Vugmeyster ◽

Dan Fai Au ◽

Dmitry Ostrovsky ◽

Yan Sun ◽

...

Keyword(s):

Molecular Structure ◽

Amyloid Fibril ◽

Amyloid Plaques ◽

Wild Type ◽

Structural Polymorphism ◽

Significant Difference ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Stability ◽

Seeding Efficiency

The structural polymorphism in β-amyloid (Aβ) plaques from Alzheimer disease (AD) has been recognized as an important pathological factor. Plaques from sporadic AD patients contain fibrillar deposits of various amyloid proteins/peptides, including posttranslational modified Aβ (PTM-Aβ) subtypes. Although many PTM-Aβs were shown to accelerate the fibrillation process, increase neuronal cytotoxicity of aggregates, or enhance the stability of fibrils, the contribution of PTM-Aβs to structural polymorphisms and their pathological roles remains unclear. We report here the NMR-based structure for the Ser-8-phosphorylated 40-residue Aβ (pS8-Aβ40) fibrils, which shows significant difference to the wild-type fibrils, with higher cross-seeding efficiency and thermodynamic stability. Given these physicochemical properties, the structures originated from pS8-Aβ40 fibrils may potentially dominate the polymorphisms in the mixture of wild-type and phosphorylated Aβ deposits. Our results imply that Aβ subtypes with “seeding-prone” properties may influence the polymorphisms of amyloid plaques through the cross-seeding process.

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ROSETTA-informed design of structurally stabilized cyclic anti-amyloid peptides

Protein Engineering Design and Selection ◽

10.1093/protein/gzz016 ◽

2019 ◽

Vol 32 (2) ◽

pp. 47-57 ◽

Cited By ~ 2

Author(s):

Chandler B Est ◽

Parth Mangrolia ◽

Regina M Murphy

Keyword(s):

Amyloid Fibril ◽

Cyclic Peptide ◽

Bond Formation ◽

Amyloid Peptides ◽

Linear Peptide ◽

Toxic Species ◽

Disulfide Linkages ◽

Amyloid Oligomers ◽

Β Amyloid ◽

Β Sheet

Abstract β-amyloid oligomers are thought to be the most toxic species formed en route to fibril deposition in Alzheimer’s disease. Transthyretin is a natural sequestering agent of β-amyloid oligomers: the binding site to β-amyloid has been traced to strands G/H of the inner β-sheet of transthyretin. A linear peptide, with the same primary sequence as the β-amyloid binding domain on transthyretin, was moderately effective at inhibiting β-amyloid fibril growth. Insertion of a β-turn template and cyclization greatly increased stability against proteolysis and improved efficacy as an amyloid inhibitor. However, the cyclic peptide still contained a significant amount of disorder. Using the Simple Cyclic Peptide Application within ROSETTA as an in silico predictor of cyclic peptide conformation and stability, we investigated putative structural enhancements, including stabilization by disulfide linkages and insertion of a second β-turn template. Several candidates were synthesized and tested for secondary structure and ability to inhibit β-amyloid aggregation. The results demonstrate that cyclization, β-sheet structure and conformational homogeneity are all preferable design features, whereas disulfide bond formation across the two β-strands is not preferable.

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