pH-Dependent Amyloid and Protofibril Formation by the ABri Peptide of Familial British Dementia

Srinivasan, Rekha; Jones, Eric M.; Liu, Keqian; Ghiso, Jorge; Marchant, Roger; Zagorski, Michael G.

doi:10.1016/j.jmb.2003.09.001

Cited by 85 publications

(75 citation statements)

References 90 publications

(136 reference statements)

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“…The ABri amyloid peptide is formed by the 34 C-terminal amino acid residues of the mutant precursor protein BRI-277, presumably generated from furin-like processing [249]. Thus, the point mutation at the stop codon of BRI results in the generation of the 34 residue ABri peptide (instead of the shorter 23 residue WT peptide), which is deposited as amyloid fibrils causing neuronal dysfunction and dementia [250]. It has been emphasized that athough FBD and AD share almost identical neurofibrillar pathology and neuronal loss that co-localize with amyloid deposits, the primary sequences of the amyloid proteins (ABri and Aβ) differ.…”

Section: Abri Peptide and Familial British Dementiamentioning

confidence: 99%

“…It has been emphasized that athough FBD and AD share almost identical neurofibrillar pathology and neuronal loss that co-localize with amyloid deposits, the primary sequences of the amyloid proteins (ABri and Aβ) differ. Therefore, ABri and Aβ amyloid deposition in the brain can trigger similar neuropathological changes (neuronal loss and dementia) and thus may be a key event in the initiation of neurodegeneration [250].…”

Section: Abri Peptide and Familial British Dementiamentioning

confidence: 99%

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Amyloidogenesis of Natively Unfolded Proteins

Uversky

2008

CAR

174

152

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Aggregation and subsequent development of protein deposition diseases originate from conformational changes in corresponding amyloidogenic proteins. The accumulated data support the model where protein fibrillogenesis proceeds via the formation of a relatively unfolded amyloidogenic conformation, which shares many structural properties with the pre-molten globule state, a partially folded intermediate first found during the equilibrium and kinetic (un)folding studies of several globular proteins and later described as one of the structural forms of natively unfolded proteins. The flexibility of this structural form is essential for the conformational rearrangements driving the formation of the core cross-beta structure of the amyloid fibril. Obviously, molecular mechanisms describing amyloidogenesis of ordered and natively unfolded proteins are different. For ordered protein to fibrillate, its unique and rigid structure has to be destabilized and partially unfolded. On the other hand, fibrillogenesis of a natively unfolded protein involves the formation of partially folded conformation; i.e., partial folding rather than unfolding. In this review recent findings are surveyed to illustrate some unique features of the natively unfolded proteins amyloidogenesis.

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Section: Abri Peptide and Familial British Dementiamentioning

confidence: 99%

Section: Abri Peptide and Familial British Dementiamentioning

confidence: 99%

Amyloidogenesis of Natively Unfolded Proteins

Uversky

2008

CAR

174

152

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“…In the same spirit, two extra hydrophobic residues in Aβ1-42 are believed to contribute to the more pronounced oligomerization and faster fibrillization compared with its alloform Aβ1-40 (24,25,40). Temperature, pH, and concentration of certain metals also affect oligomerization and pathways of fibrillization (41)(42)(43)(44).…”

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confidence: 99%

Crucial role of nonspecific interactions in amyloid nucleation

Šarić

Chebaro

Knowles

et al. 2014

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

175

172

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Protein oligomers have been implicated as toxic agents in a wide range of amyloid-related diseases. However, it has remained unsolved whether the oligomers are a necessary step in the formation of amyloid fibrils or just a dangerous byproduct. Analogously, it has not been resolved if the amyloid nucleation process is a classical onestep nucleation process or a two-step process involving prenucleation clusters. We use coarse-grained computer simulations to study the effect of nonspecific attractions between peptides on the primary nucleation process underlying amyloid fibrillization. We find that, for peptides that do not attract, the classical one-step nucleation mechanism is possible but only at nonphysiologically high peptide concentrations. At low peptide concentrations, which mimic the physiologically relevant regime, attractive interpeptide interactions are essential for fibril formation. Nucleation then inevitably takes place through a two-step mechanism involving prefibrillar oligomers. We show that oligomers not only help peptides meet each other but also, create an environment that facilitates the conversion of monomers into the β-sheet-rich form characteristic of fibrils. Nucleation typically does not proceed through the most prevalent oligomers but through an oligomer size that is only observed in rare fluctuations, which is why such aggregates might be hard to capture experimentally. Finally, we find that the nucleation of amyloid fibrils cannot be described by classical nucleation theory: in the two-step mechanism, the critical nucleus size increases with increases in both concentration and interpeptide interactions, which is in direct contrast with predictions from classical nucleation theory.amyloid | protein aggregation | protein oligomers | neurodegeneration | coarse-grained simulations D uring the process of amyloid formation, normally soluble proteins assemble into fibrils that are enriched in β-sheet content and have diameters of a few nanometers and lengths up to several micrometers. This phenomenon has been implicated in a variety of pathogenic processes, including Alzheimer's and Parkinson's diseases, type 2 diabetes, and systemic amyloidoses (1-3). The association with human diseases has largely motivated a long-standing effort to probe the assembly process, and numerous studies have aimed at elucidating the mechanism of amyloid aggregation (4). The basic nature of the aggregation reaction has emerged as a nucleation and growth process (5, 6), where the aggregates are created through a not well-understood primary nucleation event and can grow by recruiting additional peptides or proteins to their ends (7,8). In this paper, we focus on the nature of this primary step in amyloid nucleation and the fundamental initial events that underlie amyloid formation.Amyloidogenic peptides and proteins, when in their nonpathological cellular form, can range in the structures from mainly α-helical to β-sheet and even random coil, whereas the amyloid forms of proteins possess a generic cross-β-structure ...

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“…Cyclized Monomer and Cross-linked Oligomers-Cysteine-containing peptides are prone to atmospheric oxidation (30), and ABri is known to aggregate (10,31). Thus to reduce any oxidized cysteines and to disassemble any pre-existing aggregates we incubated both Bri and ABri peptides in a buffer containing ␤ME and GdmHCl prior to analysis by size exclusion chromatography (Fig.…”

Section: Oxidation Of Bri Leads To Formation Of a Cyclized Monomer Wmentioning

confidence: 99%

The Familial British Dementia Mutation Promotes Formation of Neurotoxic Cystine Cross-linked Amyloid Bri (ABri) Oligomers

Cantlon

Frigerio

Freir

et al. 2015

Journal of Biological Chemistry

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Background: Familial British dementia is a disorder similar to Alzheimer disease and is believed to be caused by the ABri peptide. Results: Cystine-linked oligomers of ABri are toxic to neurons and block long-term potentiation. Conclusion:The type and toxicity of ABri assemblies depends on cystine bond formation. Significance: ABri offers a tractable system to study the structure of disease-causing oligomers.

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pH-Dependent Amyloid and Protofibril Formation by the ABri Peptide of Familial British Dementia

Cited by 85 publications

References 90 publications

Amyloidogenesis of Natively Unfolded Proteins

Amyloidogenesis of Natively Unfolded Proteins

Crucial role of nonspecific interactions in amyloid nucleation

The Familial British Dementia Mutation Promotes Formation of Neurotoxic Cystine Cross-linked Amyloid Bri (ABri) Oligomers

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