Infectious and Noninfectious Amyloids of the HET‐s(218–289) Prion Have Different NMR Spectra

Wasmer, Christian; Soragni, Alice; Sabaté, Raimon; Lange, Adam; Riek, Roland; Meier, Beat H.

doi:10.1002/anie.200704896

Cited by 51 publications

(55 citation statements)

References 21 publications

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“…In detail, the hydrophobic azobenzene moieties are buried inside the oligomer and stabilize the interface of the two β-sheets, and the peptides' polar sidechains are pointing to the solvent. This "hydrophobic-in" and "polar-out" arrangement of the sidechains is similar to those found in amyloid fibril models obtained from solid state NMR data [58][59][60] . The assembly is stabilized by a variety of intermolecular interactions.…”

Section: Discussionsupporting

confidence: 82%

Photocontrol of Reversible Amyloid Formation with a Minimal-Design Peptide

et al. 2012

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Amyloid aggregates are highly ordered fibrillar assemblies of polypeptides involved in a number of neurodegenerative diseases. Very little is known on the pathways of self-assembly of peptides into the final amyloid fibrils, which is due in part to the difficulty of triggering the aggregation process in a controlled manner. Here we present the design and validation of a cross-linked hexapeptide that reversibly aggregates and dissociates under ultraviolet light irradiation control. First molecular dynamics simulations were carried out to identify, among hundreds of possible sequences, those with the highest propensity to form ordered (-sheet) oligomers in the trans state of the azobenzene cross-linker, and at the same time with the highest solubility in the cis state. In the simulations, the peptides were observed to spontaneously form ordered oligomers with cross-contacts when the cross-linker was in the trans state, whereas in the cis state they self-assemble into amorphous aggregates. For the most promising sequence emerging from the simulations (Ac-Cys-His-Gly-Gln-Cys-Lys-NH2 cross-linked at the two cysteine residues), the photoisomerization of the azobenzene group was shown to induce reversible aggregation by time-resolved light scattering and fluorescence measurements. The amyloid-like fibrillar topology was confirmed by electron microscopy. Potential applications of minimally designed peptides with photoswitchable amyloidogenic propensity are briefly discussed. AbstractAmyloid aggregates are highly ordered fibrillar assemblies of polypeptides involved in a number of neurodegenerative diseases. Very little is known on the pathways of self-assembly of peptides into the final amyloid fibrils, which is due in part to the difficulty of triggering the aggregation process in a controlled manner. Here we present the design and validation of a cross-linked hexapeptide that reversibly aggregates and dissociates under ultraviolet light irradiation control. First molecular dynamics simulations were carried out to identify, among hundreds of possible sequences, those with the highest propensity to form ordered (β-sheet) oligomers in the trans state of the azobenzene cross-linker, and at the same time with the highest solubility in the cis state. In the simulations, the peptides were observed to spontaneously form ordered oligomers with cross-β contacts when the cross-linker was in the trans state, whereas in the cis state they self-assemble into amorphous aggregates. For the most promising sequence emerging from the simulations (Ac-Cys-His-Gly-GlnCys-Lys-NH 2 cross-linked at the two cysteine residues), the photo-isomerization of the azobenzene group was shown to induce reversible aggregation by time-resolved light scattering and fluorescence measurements. The amyloid-like fibrillar topology was confirmed by electron microscopy. Potential applications of minimally-designed peptides with photoswitchable amyloidogenic propensity are briefly discussed.

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Section: Discussionsupporting

confidence: 82%

Photocontrol of Reversible Amyloid Formation with a Minimal-Design Peptide

et al. 2012

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“…5 A and B). Both have been found to have features characteristic of amyloid (11). The helical symmetries initially assigned were obtained by measuring the distance between crossover points, which corresponds to a 120°rotation around the central axis for a protofibril.…”

Section: Comparing the Singlet Fibril Reconstruction And The Ssnmr-dementioning

confidence: 99%

“…The PD is necessary and sufficient for prion formation and fibrillizes readily in vitro (9)(10)(11). The HeLo domain interacts with the PD to affect its fibrillation but as yet has no other assigned function (6).…”

mentioning

confidence: 99%

Structural dependence of HET-s amyloid fibril infectivity assessed by cryoelectron microscopy

Mizuno

Baxa

Steven

2011

Proc. Natl. Acad. Sci. U.S.A.

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HET-s is a prion protein of the fungus Podospora anserina which, in the prion state, is active in a self/nonself recognition process called heterokaryon incompatibility. Its prionogenic properties reside in the C-terminal "prion domain." The HET-s prion domain polymerizes in vitro into amyloid fibrils whose properties depend on the pH of assembly; above pH 3, infectious singlet fibrils are produced, and below pH 3, noninfectious triplet fibrils. To investigate the correlation between structure and infectivity, we performed cryo-EM analyses. Singlet fibrils have a helical pitch of approximately 410 Å and a left-handed twist. Triplet fibrils have three protofibrils whose lateral dimensions (36 × 25 Å) and axial packing (one subunit per 9.4 Å) match those of singlets but differ in their supercoiling. At 8.5-Å resolution, the cross-section of the singlet fibril reconstruction is largely consistent with that of a β-solenoid model previously determined by solid-state NMR. Reconstructions of the triplet fibrils show three protofibrils coiling around a common axis and packed less tightly at pH 3 than at pH 2, eventually peeling off. Taken together with the earlier observation that fragmentation of triplet fibrils by sonication does not increase infectivity, these observations suggest a novel mechanism for self-propagation, whereby daughter fibrils nucleate on the lateral surface of singlet fibrils. In triplets, this surface is occluded, blocking nucleation and thereby explaining their lack of infectivity. assembly nucleation | cryoelectron microscopy | protein template | polymorphism | three-dimensional image reconstruction

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“…This aspect has extremely important consequences for our understanding and recent solid state NMR studies of the fungal HET-s protein at pH 3 versus pH 7 29 . This evolutionarily optimized robustness of design means that amyloid can be used as reliable building material in materials ranging from the cement of barnacle adhesive plaques 30 to templates for gold nanowires 31 and biomimetic silks in materials and medical applications.…”

Section: The Hows Of Functional Amyloid: Policing the Massesmentioning

confidence: 99%

Functional amyloid

Otzen

2010

Prion

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Infectious and Noninfectious Amyloids of the HET‐s(218–289) Prion Have Different NMR Spectra

Cited by 51 publications

References 21 publications

Photocontrol of Reversible Amyloid Formation with a Minimal-Design Peptide

Photocontrol of Reversible Amyloid Formation with a Minimal-Design Peptide

Structural dependence of HET-s amyloid fibril infectivity assessed by cryoelectron microscopy

Functional amyloid

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