Amyloid formation under physiological conditions proceeds via a native-like folding intermediate

Jahn, Thomas R.; Parker, Martin J.; Homans, Steve W.; Radford, Sheena E.

doi:10.1038/nsmb1058

Cited by 303 publications

(496 citation statements)

References 48 publications

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“…These results parallel the observation that protein aggregation and amyloid fiber formation may arise from accumulation of partially folded intermediates [12] …”

Section: Accepted M Manuscriptsupporting

confidence: 86%

“…These are particularly difficult tasks considering the fact that folding intermediates are often only transiently populated and play different mechanistic roles, being either on-pathway productive species, or offpathway kinetic traps that have to unfold for proper folding to take place. Furthermore, it has been suggested that accumulation of folding intermediates may be a crucial step prior to protein aggregation and amyloid fiber formation [12], posing the characterization of these partially structured species as a central problem in structural biology.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

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Identification and characterization of protein folding intermediates

Gianni

Ivarsson

Jemth

et al. 2007

Biophysical Chemistry

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In order to understand the mechanism by which a polypeptide chain folds into its functionally active native state it is necessary to characterize in detail all the species accumulated along the pathway.The elusive nature of protein folding intermediates poses their identification and characterization as an extremely difficult task in the protein folding field. In the case of small single domain proteins, the direct measurement of the thermodynamics and structural parameters of protein folding intermediates has provided new insights on the nature of the forces involved in the stabilization of nascent protein structures. Here we summarize some of the experimental approaches aimed at the detection and characterization of folding intermediates along with a discussion of some general structural features emerging from these studies.

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“…These results parallel the observation that protein aggregation and amyloid fiber formation may arise from accumulation of partially folded intermediates [12] …”

Section: Accepted M Manuscriptsupporting

confidence: 86%

Section: Accepted M Manuscriptmentioning

confidence: 99%

Identification and characterization of protein folding intermediates

Gianni

Ivarsson

Jemth

et al. 2007

Biophysical Chemistry

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show abstract

“…In particular, highly abundant proteins with relatively low solubilities are prone to aggregate [88]. An increasing number of neurodegenerative and other varieties of prion and amyloid diseases are now known to be caused by misfolded structures (different 'native' structures) or by aggregation/oligomerization of intermediate conformational states, with propensity for misfolding increased by certain mutations [87,89] (figure 3). Cataracts in the human eye are also found to be caused by accumulation of misfolded proteins [90] and associated with mutations that led to abnormal folding behaviour [91,92].…”

Section: Biophysical Consequences Of Protein Mutations 21 Mutationamentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

220

207

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The study of molecular evolution at the level of protein-coding genes often entails comparing large datasets of sequences to infer their evolutionary relationships. Despite the importance of a protein's structure and conformational dynamics to its function and thus its fitness, common phylogenetic methods embody minimal biophysical knowledge of proteins. To underscore the biophysical constraints on natural selection, we survey effects of protein mutations, highlighting the physical basis for marginal stability of natural globular proteins and how requirement for kinetic stability and avoidance of misfolding and misinteractions might have affected protein evolution. The biophysical underpinnings of these effects have been addressed by models with an explicit coarse-grained spatial representation of the polypeptide chain. Sequence-structure mappings based on such models are powerful conceptual tools that rationalize mutational robustness, evolvability, epistasis, promiscuous function performed by 'hidden' conformational states, resolution of adaptive conflicts and conformational switches in the evolution from one protein fold to another. Recently, protein biophysics has been applied to derive more accurate evolutionary accounts of sequence data. Methods have also been developed to exploit sequence-based evolutionary information to predict biophysical behaviours of proteins. The success of these approaches demonstrates a deep synergy between the fields of protein biophysics and protein evolution.

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“…The occurrence of just a few intermolecular contacts, in a quasi-native folding intermediate, would be sufficient to drive the assembly of amyloids (25)(26)(27)(28). In the light of the previous work on DNA-induced transformation of RepA (20,22,23), there is an inverse correlation between the magnitude of the structural change elicited by each dsDNA sequence (iteron Ն nonspecific Ͼ operator) and the internal order of the resulting WH1-A31V assemblies (irregular Ͻ spheroids Ͻ fibrils).…”

Section: Discussionmentioning

confidence: 99%

Defined DNA sequences promote the assembly of a bacterial protein into distinct amyloid nanostructures

Giraldo

2007

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

171

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RepA, the replication initiator protein of Pseudomonas pPS10 plasmid, is made of two winged-helix (WH) domains. RepA dimers undergo a structural transformation upon binding to origin DNA sequences (iterons), resulting in monomerization and ␣-helix into ␤-strand conversion. This affects the N-terminal domain (WH1) and generates a metastable intermediate. Here it is shown that the interaction of short dsDNA oligonucleotides, including iteron or operator RepA targets, with the isolated WH1 domain promotes the assembly of different nanostructures. These range from irregular aggregates to amyloid spheroids and fibers. Their intrinsic order inversely correlates with the extent of the transformation induced by each DNA sequence on RepA. However, DNA is not a constituent of the assembled fibers, in agreement with the protein-only principle for amyloid structure. Thus, the RepA-WH1 domain on DNA binding mimics the behavior of the mammalian prion protein. The stretch of amino acids responsible for WH1 aggregation has been identified, leading to the design of mutants with enhanced or reduced amyloidogenicity and the synthesis of a peptide that assembles into a cross-␤ structure. RepA amyloid assemblies could have a role in the negative regulation of plasmid replication. This article underlines the potential of specific nucleic acid sequences in promoting protein amyloidogenesis at nearly physiological conditions. amyloidogenesis ͉ conformational changes ͉ DNA binding ͉ fiber assembly ͉ RepA protein T he formation of protein assemblies with amyloid properties is a subject of intense research because of their involvement in severe human diseases (1, 2). An unsolved issue is the nature of the signal(s) responsible for amyloidogenesis, which includes proteolytic processing of a functional precursor and mutations, and also hyperphosphorylation (3) or the binding to elements of the cell envelope (4) or nucleic acids (5-8). The major (if not the only) component of any mature amyloid assembly is protein (9, 10). The studies of amyloidogenesis have been extended to model systems based in proteins not involved in any disease (1).Our current understanding of protein aggregation into amyloids suggests that some partially unfolded intermediates that populate the funnel-shaped folding energy landscape of virtually any protein aggregate into a stable, low-energy conformation distinct from the protein native state (1, 2). Supramolecular assembly is a common functional resource for proteins by using an ample repertoire of protein-protein interfaces. However, the family of structures responsible for the unique staining (11) and diffraction (12) properties of any protein amyloid is known as cross-␤: a ␤-sheet of indefinite length is formed by the stacking, orthogonal to its axis, of ␤-strands from each protein monomer (13). Amyloidogenesis often includes the refolding as ␤-strands of protein regions that, although compatible with such secondary structure, are found as ␣-helices or coils in the native structure (14-18). In other cases, nearly...

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Amyloid formation under physiological conditions proceeds via a native-like folding intermediate

Cited by 303 publications

References 48 publications

Identification and characterization of protein folding intermediates

Identification and characterization of protein folding intermediates

Biophysics of protein evolution and evolutionary protein biophysics

Defined DNA sequences promote the assembly of a bacterial protein into distinct amyloid nanostructures

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