FTIR reveals structural differences between native β‐sheet proteins and amyloid fibrils

Zandomeneghi, Giorgia; Krebs, Mark R.H.; McCammon, Margaret G.; Fändrich, Marcus

doi:10.1110/ps.041024904

Cited by 644 publications

(593 citation statements)

References 63 publications

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“…This shift is interesting because it indicates an increase of the number of b-strands involved the b-sheet and/or the formation of stronger H-bonding (i.e. shorter H-bonds) [38,39] as expected in extremely stable structure such as fibrils.…”

Section: Secondary Structure Changes Occurring During Aggregationmentioning

confidence: 76%

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

137

119

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Alzheimer's disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely accepted that the amyloid beta peptide (Ab) aggregation and especially the oligomeric states rather than fibrils are involved in AD onset. We used infrared spectroscopy to provide structural information on the entire aggregation pathway of Ab(1-40), starting from monomeric Ab to the end of the process, fibrils. Our structural study suggests that conversion of oligomers into fibrils results from a transition from antiparallel to parallel b-sheet. These structural changes are described in terms of H-bonding rupture/formation, b-strands reorientation and b-sheet elongation. As antiparallel b-sheet structure is also observed for other amyloidogenic proteins forming oligomers, reorganization of the b-sheet implicating a reorientation of b-strands could be a generic mechanism determining the kinetics of protein misfolding. Elucidation of the process driving aggregation, including structural transitions, could be essential in a search for therapies inhibiting aggregation or disrupting aggregates.

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Section: Secondary Structure Changes Occurring During Aggregationmentioning

confidence: 76%

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

137

119

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“…Hence, it appears that there is a very similar ␤-sheet structure adopted throughout the molecular weight range of all the oligomeric species formed. Some indication of the nature of the ␤-sheet structure can be gleaned from Fourier transform infrared spectra of soluble ␤-PrP, albeit from mouse, which are similar to those of ordered fibrils but with a less pronounced 1622 cm Ϫ1 maximum characteristic of ␤-amyloid (40), rather than the amide I peak in the region of 1630 to 1643 cm Ϫ1 , which is typical of natively folded ␤-sheet proteins (75). This suggests that the ␤-sheet contacts in the soluble, oligomeric forms of ␤-PrP are non-native and amyloid-like, and that the ␤-PrP oligomeric species are direct fibril precursors.…”

Section: Resultsmentioning

confidence: 99%

Conformational Properties of β-PrP

Hosszu

Trevitt

Jones

et al. 2009

Journal of Biological Chemistry

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Prion propagation involves a conformational transition of the cellular form of prion protein (PrP C ) to a disease-specific isomer (PrP Sc ), shifting from a predominantly ␣-helical conformation to one dominated by ␤-sheet structure. This conformational transition is of critical importance in understanding the molecular basis for prion disease. Here, we elucidate the conformational properties of a disulfide-reduced fragment of human PrP spanning residues 91-231 under acidic conditions, using a combination of heteronuclear NMR, analytical ultracentrifugation, and circular dichroism. We find that this form of the protein, which similarly to PrP Sc , is a potent inhibitor of the 26 S proteasome, assembles into soluble oligomers that have significant ␤-sheet content. The monomeric precursor to these oligomers exhibits many of the characteristics of a molten globule intermediate with some helical character in regions that form helices I and III in the PrP C conformation, whereas helix II exhibits little evidence for adopting a helical conformation, suggesting that this region is a likely source of interaction within the initial phases of the transformation to a ␤-rich conformation. This precursor state is almost as compact as the folded PrP C structure and, as it assembles, only residues 126 -227 are immobilized within the oligomeric structure, leaving the remainder in a mobile, random-coil state.

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“…FTIR spectra from various amyloid fibrils display characteristic β-sheet peaks near 1620 cm −1 wavenumber that are distinct from the range of peak wavenumbers for native β-sheet folds. 18 Since the Amide-I region of the FTIR spectrum for native lysozyme is dominated by a prominent α-helix peak near 1655 cm −1 , lysozyme represents a particularly favorable system for resolving structural features emerging within the amyloid-specific region around 1620 cm −1 . It is well-known that the kinetics signatures obtained from the amyloid indicator dye thioflavin T along the oligomer-free vs. oligomeric assembly pathway are distinct.…”

Section: Introductionmentioning

confidence: 99%

Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth

Foley

Hill

Miti

et al. 2013

The Journal of Chemical Physics

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Deposits of fibrils formed by disease-specific proteins are the molecular hallmark of such diverse human disorders as Alzheimer's disease, type II diabetes, or rheumatoid arthritis. Amyloid fibril formation by structurally and functionally unrelated proteins exhibits many generic characteristics, most prominently the cross β-sheet structure of their mature fibrils. At the same time, amyloid formation tends to proceed along one of two separate assembly pathways yielding either stiff monomeric filaments or globular oligomers and curvilinear protofibrils. Given the focus on oligomers as major toxic species, the very existence of an oligomer-free assembly pathway is significant. Little is known, though, about the structure of the various intermediates emerging along different pathways and whether the pathways converge towards a common or distinct fibril structures. Using infrared spectroscopy we probed the structural evolution of intermediates and late-stage fibrils formed during in vitro lysozyme amyloid assembly along an oligomeric and oligomer-free pathway. Infrared spectroscopy confirmed that both pathways produced amyloid-specific β-sheet peaks, but at pathwayspecific wavenumbers. We further found that the amyloid-specific dye thioflavin T responded to all intermediates along either pathway. The relative amplitudes of thioflavin T fluorescence responses displayed pathway-specific differences and could be utilized for monitoring the structural evolution of intermediates. Pathway-specific structural features obtained from infrared spectroscopy and Thioflavin T responses were identical for fibrils grown at highly acidic or at physiological pH values and showed no discernible effects of protein hydrolysis. Our results suggest that late-stage fibrils formed along either pathway are amyloidogenic in nature, but have distinguishable structural fingerprints. These pathway-specific fingerprints emerge during the earliest aggregation events and persist throughout the entire cascade of aggregation intermediates formed along each pathway. © 2013 AIP Publishing LLC. [http://dx

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FTIR reveals structural differences between native β‐sheet proteins and amyloid fibrils

Cited by 644 publications

References 63 publications

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Conformational Properties of β-PrP

Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth

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