Polymorphism in an Amyloid‐Like Fibril‐Forming Model Peptide

Verel, René; Tomka, I.; Bertozzi, Carlo; Cadalbert, Riccardo; Kammerer, Richard A.; Steinmetz, Michel O.; Meier, Beat H.

doi:10.1002/anie.200800021

Cited by 53 publications

(49 citation statements)

References 23 publications

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“…This work proved that the molecular structure in amyloid fibrils is generally not determined uniquely by the amino acid sequence of the fibril-forming polypeptide. Similar polymorphism has now been documented by solid state NMR for α-synuclein fibrils (51), amylin fibrils (13, 14), and other amyloid fibrils (40, 52). …”

Section: β-Amyloid Fibrils and Prefibrillar Aggregatessupporting

confidence: 71%

Solid-State NMR Studies of Amyloid Fibril Structure

Tycko

2011

Annu. Rev. Phys. Chem.

513

483

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Current interest in amyloid fibrils stems from their involvement in neurodegenerative and other diseases and from their role as an alternative structural state for many peptides and proteins. Solid state NMR methods have the unique capability of providing detailed structural constraints for amyloid fibrils, sufficient for the development of full molecular models. In this article, recent progress in the application of solid state NMR to fibrils associated with Alzheimer’s disease, prion fibrils, and related systems is reviewed, along with relevant developments in solid state NMR techniques and technology.

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Section: β-Amyloid Fibrils and Prefibrillar Aggregatessupporting

confidence: 71%

Solid-State NMR Studies of Amyloid Fibril Structure

Tycko

2011

Annu. Rev. Phys. Chem.

513

483

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“…Discussion It is well documented that fibril morphology depends on environmental conditions, e.g., pH, temperature, and agitation (9,(17)(18)(19)(20)(21). However, even under the same conditions and within the same sample, variation of the fibril morphology may exist.…”

Section: Populations and Relative Stabilities For Aβ 42 Tubular Modelmentioning

confidence: 86%

Hollow core of Alzheimer’s A β ₄₂ amyloid observed by cryoEM is relevant at physiological pH

Miller

Tsai

et al. 2010

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

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Recent cryoEM density maps of A β 42 fibrils obtained at low pH revealed two protofilaments winding around a hollow core raising the question if such tubular structures also exist at physiological pH. Based on the cryoEM measurements and on NMR data, we probe amyloid fibril organizations corresponding to the observed cryoEM density map. Our study demonstrates that the tubular A β 42 fibril models exist at both acidic and physiological pH; however, the relative populations of the polymorphic models shift with pH. At acidic pH, the hollow core model exhibits higher population than the other models; at physiological pH, although it is less populated compared to the other models, structurally, it is stable and represents 8% of the population. We observe that only models with C termini facing the external surface of the fibril retain the hollow core under acidic and physiological conditions with dimensions similar to those observed by cryoEM; on the other hand, the hydrophobic effect shrinks the tubular cavity in the alternative organization. The existence of the hollow core fibril at physiological pH emphasizes the need to examine toxic effects of minor oligomeric species with unique organizations.

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“…A mixture of singly 15 N- and 13 C-labeled peptides was used to determine 13 C- 15 N distances via 1D REDOR(55) and 2D TEDOR(56, 57) experiments. Note that analogous 13 C- 13 C and 13 C- 15 N experiments have been used for the identification of inter-strand contacts in other amyloids(58-60). These intermolecular distance measurements consistently show that the Gly-7 residue of different monomers is in close proximity, and in a site-specific fashion show that G7-G7 intermolecular interactions only occur between identical fibril conformers (i.e.…”

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confidence: 99%

Structural Characterization of GNNQQNY Amyloid Fibrils by Magic Angle Spinning NMR

2010

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Several human diseases are associated with the formation of amyloid aggregates, but experimental characterization of these amyloid fibrils and their oligomeric precursors has remained challenging. Experimental and computational analysis of simpler model systems has therefore been necessary, for instance on the peptide fragment GNNQQNY 7-13 of yeast prion protein Sup35p. Expanding on a previous publication, we report here a detailed structural characterization of GNNQQNY fibrils using magic angle spinning (MAS) NMR. Based on additional chemical shift assignments we confirm the coexistence of three distinct peptide conformations within the fibrillar samples, as reflected in substantial chemical shift differences. Backbone torsion angle measurements indicate that the basic structure of these co-existing conformers is an extended β-sheet. We structurally characterize a previously identified localized distortion of the β-strand backbone specific to one of the conformers. Intermolecular contacts are consistent with each of the conformers being present in its own parallel and in-register sheet. Overall the MAS NMR data indicate a substantial † This research was supported by the National Institutes of Health through grants EB-003151 and EB-002026. Supporting Information Available: Assignment spectra, Tyr chemical shifts, and chemical shift comparisons to the crystals; CSI and TALOS data for the fibrils; additional experimental details on the MAS NMR experiments; additional details on the torsion angle data and analyses; schematics of the inter-strand, intra-sheet contacts in in-register parallel β-sheets; backbone schematics for the fibril conformers. These supplemental materials may be accessed free of charge online at http://pubs.acs.org. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript difference between the structure of the fibrillar and crystalline forms of these peptides, with a clear increased complexity in the GNNQQNY fibril structure. These experimental data can provide guidance for future work, both experimental and theoretical, and provide insights into the distinction between fibril growth and crystal formation.There are more than 20 human diseases, include Alzheimer's, Parkinson's and Huntington's diseases (1), that are associated with the formation of amyloid fibrils, through the misfolding and aggregation of different amyloidogenic proteins. To further our understanding of these diseases, which affect increasingly large fractions of the population, it is essential to understand the misfolding process, in terms of the mechanism of fibril formation as well as the structural features of the resulting aggregates. Unfortunately, it has proven challenging to obtain structural information on the highly stable but insoluble and non-crystalline amyloid or amyloid-like fibrils, because they do not diffract to high resolution and are insoluble. Thus, the two major techniques used in structural biology, X-ray diffraction and solution NMR, are not applicable to these systems. The step...

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Polymorphism in an Amyloid‐Like Fibril‐Forming Model Peptide

Cited by 53 publications

References 23 publications

Solid-State NMR Studies of Amyloid Fibril Structure

Solid-State NMR Studies of Amyloid Fibril Structure

Hollow core of Alzheimer’s A β ₄₂ amyloid observed by cryoEM is relevant at physiological pH

Structural Characterization of GNNQQNY Amyloid Fibrils by Magic Angle Spinning NMR

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Polymorphism in an Amyloid‐Like Fibril‐Forming Model Peptide

Cited by 53 publications

References 23 publications

Solid-State NMR Studies of Amyloid Fibril Structure

Solid-State NMR Studies of Amyloid Fibril Structure

Hollow core of Alzheimer’s A β 42 amyloid observed by cryoEM is relevant at physiological pH

Structural Characterization of GNNQQNY Amyloid Fibrils by Magic Angle Spinning NMR

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Hollow core of Alzheimer’s A β ₄₂ amyloid observed by cryoEM is relevant at physiological pH