Core Structure of Amyloid Fibrils Formed by Residues 106–126 of the Human Prion Protein

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Background: Nonfibrillar amyloid oligomers are cytotoxic and may act through physical disruption of cell membranes. Results: Cytotoxic oligomers of the amyloid peptide PrP(106 -126) disrupt membranes through distinct mechanisms, depending on lipid composition. Conclusion: Cytotoxicity of PrP(106 -126) oligomers can occur through at least two different physical processes. Significance: Mechanisms for the membrane disruption of amyloid oligomers are proposed, providing new insight into their cytotoxicity.

supporting

confidence: 82%

The Mechanism of Membrane Disruption by Cytotoxic Amyloid Oligomers Formed by Prion Protein(106–126) Is Dependent on Bilayer Composition

Walsh

Vanderlee

Yau

et al. 2014

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“…Here, it is worth noting that recent studies have suggested similar features in other proteins. For ␤2m and prion proteins, domain-swapped dimers have been observed (19,20), but for both proteins ssNMR and ESR studies on fibrils have indicated an IP sheet structure and a loss of the native conformation (51,(62)(63)(64)(65). Thus, at least in a number of cases, similar observations have been made, when mature fibrils were studied directly.…”

Section: Discussionmentioning

confidence: 76%

Amyloid-like Fibrils from a Domain-swapping Protein Feature a Parallel, in-Register Conformation without Native-like Interactions

Hoop

Kodali

et al. 2011

The formation of amyloid-like fibrils is characteristic of various diseases, but the underlying mechanism and the factors that determine whether, when, and how proteins form amyloid, remain uncertain. Certain mechanisms have been proposed based on the three-dimensional or runaway domain swapping, inspired by the fact that some proteins show an apparent correlation between the ability to form domain-swapped dimers and a tendency to form fibrillar aggregates. Intramolecular ␤-sheet contacts present in the monomeric state could constitute intermolecular ␤-sheets in the dimeric and fibrillar states. One example is an amyloid-forming mutant of the immunoglobulin binding domain B1 of streptococcal protein G, which in its native conformation consists of a four-stranded ␤-sheet and one ␣-helix. Under native conditions this mutant adopts a domainswapped dimer, and it also forms amyloid-like fibrils, seemingly in correlation to its domain-swapping ability. We employ magic angle spinning solid-state NMR and other methods to examine key structural features of these fibrils. Our results reveal a highly rigid fibril structure that lacks mobile domains and indicate a parallel in-register ␤-sheet structure and a general loss of native conformation within the mature fibrils. This observation contrasts with predictions that native structure, and in particular intermolecular ␤-strand interactions seen in the dimeric state, may be preserved in "domain-swapping" fibrils. We discuss these observations in light of recent work on related amyloidforming proteins that have been argued to follow similar mechanisms and how this may have implications for the role of domain-swapping propensities for amyloid formation.Amyloid fibril formation is characteristic of a variety of human disorders, including Huntington and Alzheimer diseases (1, 2). In amyloid-related diseases, one or more proteins are found in fibrillar aggregates, in a non-native, highly ␤-sheetrich conformation. Depending on the disease context, the propensity for amyloid formation may be traced to mutations and cleavage events, combined with poorly understood external triggers. Many proteins can also be made to form amyloid fibrils in vitro. Intriguingly, there are many accounts of proteins that form amyloid-like fibrils that are not associated with pathologies (2). Whether disease-related or not, amyloid fibrils share key biochemical and biophysical characteristics, suggesting common structural features. Understanding the fibril formation pathway is of interest not only as there may be a correlation between disease onset and protein aggregation, but also because transient oligomeric precursors may act as toxic species. However, a lack of high resolution structures of most fibrils and their precursors limits our knowledge of the mechanism of formation.One seemingly common structural motif for amyloid fibrils is an in-register parallel (IP) 3 assembly into pleated ␤-sheets, stabilized by backbone-to-backbone hydrogen bonding, combined with favorable side-chain interactions (e....

“…Indeed, this sequence has been found to form amyloid in isolation (21), and structural models for amyloids of several PrP peptides containing this sequence have been presented (22,23,33). In these studies, PrP residues 113-120 have been found to adopt either parallel in-register or antiparallel ␤-structure, with Ala side chains of opposing strands packing into various "steric zippers" as described by Eisenberg and co-workers (34).…”

Section: Essential and Nonessential Regions Of Prp23-144 Amyloidmentioning

confidence: 91%

“…The latter strand contains a species-specific sequence at residues 138 -139 that determines seeding specificity (15,16). The former ␤-strand region, conversely, encompasses a conserved hydrophobic palindrome sequence, 113 AGAAAAGA 120 , which has been shown critical for amyloidogenesis of certain PrP peptides (21)(22)(23) and for propagation of pathological PrP in cell culture (24). However, * This work was supported by National Institutes of Health Grants R01NS038604 and R01NS044158 (to W. K. S.) and R01GM094357 (to C. P.…”

mentioning

confidence: 99%

Structural Polymorphism in Amyloids

Jones

Surewicz

et al. 2011

Background:The Y145Stop prion protein is a useful model for understanding basic principles of amyloid formation. Results: Deletion of the conserved palindrome sequence 113 AGAAAAGA 120 results in an altered amyloid ␤-core without affecting amyloidogenicity or seeding specificity. Conclusion:The core of some amyloids contains "essential" (nucleation-determining) and "nonessential" regions. Significance: This study reveals a novel mechanism for structural polymorphism in amyloids.