A Molecular Model of Alzheimer Amyloid β-Peptide Fibril Formation

Tjernberg, Lars O.; Callaway, David J.E.; Tjernberg, Agneta; Hahne, Solveig; Lilliehöök, Christina; Terenius, Lars; Thyberg, Johan; Nordstedt, Christer

doi:10.1074/jbc.274.18.12619

Cited by 349 publications

(371 citation statements)

References 32 publications

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“…The findings of this study are important, complementing several reports supporting that the [14 -23] A␤ sequence is critical for fibrillation [40,41], whereas the [16 -20] sequence is essential for A␤-A␤ binding and serves as a binding sequence during A␤ polymerization and fibril formation [42]. It has also been proposed that structural elements in the central hydrophobic core [17][18][19][20][21] and at the carboxy-terminus of A␤ possess a key role in controlling fibrillogenesis [34].…”

Section: Resultssupporting

confidence: 79%

Localization of the noncovalent binding site between amyloid-β-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry

Bazoti

Bergquist

Markides

et al. 2008

J. Am. Soc. Mass Spectrom.

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Abnormal accumulation and aggregation of amyloid-␤-peptide (A␤) eventually lead to the formation and cerebral deposition of amyloid plaques, the major pathological hallmark in Alzheimer's disease (AD). Oleuropein (OE), an Olea europaea L. derived polyphenol, exhibits a broad range of pharmacological properties, such as antioxidant, anti-inflammatory, and antiatherogenic, which could serve as combative mechanisms against several reported pathways involved in the pathophysiology of AD. The reported noncovalent interaction between A␤ and OE could imply a potential antiamyloidogenic role of the latter on the former via stabilization of its structure and prevention of the adaptation of a toxic ␤-sheet conformation. The established ␤-sheet conformation of the A␤ hydrophobic carboxy-terminal region and the dependence of its toxicity and aggregational propensity on its secondary structure make the determination of the binding site between A␤ and OE highly important for assessing the role of the interaction. In this study, two different proteolytic digestion protocols, in conjunction with high-sensitivity electrospray ionization mass spectrometric analysis of the resulting peptide fragments, were used to determine the noncovalent binding site of OE on A␤ and revealed the critical regions for the interaction. and its aggregational properties depend on both the peptide concentration and conformation, as well as on the solution conditions and pH [2,3]. It has been reported that reduction of the A␤ production, by controlling the cleavage of the larger transmembrane amyloid precursor protein (APP), or inhibition of its aggregation by using small molecules, which may interact noncovalently with A␤ and stabilize its structure, could serve as preventive or therapeutic approaches against AD [4]. In general, interruption of noncovalent interactions between protein and peptides, or even more between proteins/peptides and ligands can cause abnormalities, which often lead to diseases [5]. One interaction of this kind has been established between the Olea europaea derived bioactive compound, oleuropein (OE), and A␤ by means of electrospray ionization mass spectrometry (ESI-MS) [6]. This interaction could prove potent in inhibiting its aggregation.OE is a polyphenol extracted from the fruits and leaves of Olea europaea L. and possesses a wide range of pharmacological properties, such as antioxidant [7][8][9], anti-inflammatory [10, 11], antiatherogenic [12-14], antibacterial [15][16][17], and anticancer [18,19]. Moreover, OE and its metabolites have been shown to be potent against contemporary diseases, such as HIV [20,21] and osteoporosis [22,23]. Interestingly, in vitro [24] and epidemiological [25] studies demonstrated the positive impact of polyphenols on the onset of age-related disorders, such as dementia [26,27].It is regarded that the pathophysiology of AD is tangled and many theories have been proposed to illumine its mechanism. Free radical reactions and oxidative stress [28,29], as well as unregulated immune response [30,3...

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Section: Resultssupporting

confidence: 79%

Localization of the noncovalent binding site between amyloid-β-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry

Bazoti

Bergquist

Markides

et al. 2008

J. Am. Soc. Mass Spectrom.

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“…Like MAX1 fibrils, disease-associated amyloid and prion fibrils contain cross-β structures. Early models for amyloid-β (Aβ) fibrils suggested that β-hairpins might be building blocks for amyloid structures (36,37). However, subsequent solid-state NMR studies (7)(8)(9)(10)35) revealed in-register, parallel cross-β structures comprising peptide conformations in which N-terminal and C-terminal β-strand segments form separate β-sheets that contain only intermolecular hydrogen bonds, with sidechain-sidechain contacts between these β-sheets.…”

Section: Discussionmentioning

confidence: 99%

Molecular structure of monomorphic peptide fibrils within a kinetically trapped hydrogel network

Nagy-Smith

Moore

Schneider

et al. 2015

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

118

127

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Most, if not all, peptide-and protein-based hydrogels formed by self-assembly can be characterized as kinetically trapped 3D networks of fibrils. The propensity of disease-associated amyloidforming peptides and proteins to assemble into polymorphic fibrils suggests that cross-β fibrils comprising hydrogels may also be polymorphic. We use solid-state NMR to determine the molecular and supramolecular structure of MAX1, a de novo designed gelforming peptide, in its fibrillar state. We find that MAX1 adopts a β-hairpin conformation and self-assembles with high fidelity into a double-layered cross-β structure. Hairpins assemble with an in-register Syn orientation within each β-sheet layer and with an Anti orientation between layers. Surprisingly, although the MAX1 fibril network is kinetically trapped, solid-state NMR data show that fibrils within this network are monomorphic and most likely represent the thermodynamic ground state. Intermolecular interactions not available in alternative structural arrangements apparently dictate this monomorphic behavior.M AX1 is a 20-residue peptide designed de novo to fold into an amphiphilic β-hairpin that self-assembles to form a fibrillar network within a self-supporting hydrogel (1). The MAX1 gel exhibits shear thin-recovery rheological behavior (2), is cytocompatible toward mammalian cells, yet is inherently antimicrobial (3) and thus has applications in tissue engineering and drug delivery. In addition to exploring the utility of the gel, we seek to understand the mechanism of gelation, the macroscale morphology of its fibrillar network, and the underlying molecular structure of its fibrils.MAX1 contains two segments of alternating lysine and valine residues, connected by a four-residue turn-forming segment. When initially dissolved in water, electrostatic repulsions among protonated lysine sidechains lead to an ensemble of monomeric random coil conformations (1). Peptide folding and self-assembly, leading to gelation (Fig. 1), can be triggered by attenuating electrostatic repulsions, by adjusting the solution pH and/or ionic strength. Increasing the solution temperature also drives hydrophobic collapse of valine sidechains, further favoring MAX1 assembly. According to circular dichroism (1), cryo-transmission electron microscopy (TEM) (4), small-angle neutron scattering (5), and dynamic light scattering coupled with rheological measurements (4), soon after the triggering event, peptides assemble into branched clusters of β-sheet-rich, semiflexible nanofibrils throughout the solution. Individual clusters contain dangling fibril ends that grow and interpenetrate neighboring clusters as the network evolves. Multiple particle tracking microrheology shows that the time at which the fibril network percolates the entire sample volume, defining the gel point, is less than 1 min at 1% (wt/vol) peptide (6). In this mechanism of gelation, the growing fibrils become kinetically trapped in the evolving network as they percolate the sample volume. Fibrils do not precipitate, but rather ...

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“…Interestingly, it has been shown that residues 16-20 in A␤ are essential for A␤ polymerization (37).…”

Section: Avoidance Of Amyloid Fibril Formation In Proteins: Amyloid Bmentioning

confidence: 99%

Sequence determinants of amyloid fibril formation

Paz

Serrano²

2003

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

371

362

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The establishment of rules that link sequence and amyloid feature is critical for our understanding of misfolding diseases. To this end, we have performed a saturation mutagenesis analysis on the de novodesigned amyloid peptide STVIIE (1). The positional scanning mutagenesis has revealed that there is a position dependence on mutation of amyloid fibril formation and that both very tolerant and restrictive positions to mutation can be found within an amyloid sequence. In this system, mutations that accelerate ␤-sheet polymerization do not always lead to an increase of amyloid products. On the contrary, abundant fibrils are typically found for mutants that polymerize slowly. From these experiments, we have extracted a sequence pattern to identify amyloidogenic stretches in proteins. The pattern has been validated experimentally. In silico sequence scanning of amyloid proteins also supports the pattern. Analysis of protein databases has shown that highly amyloidogenic sequences matching the pattern are less frequent in proteins than innocuous amino acid combinations and that, if present, they are surrounded by amino acids that disrupt their aggregating capability (amyloid breakers). This study provides the potential for a proteome-wide scanning to detect fibril-forming regions in proteins, from which molecules can be designed to prevent and͞or disrupt this process.I t is accepted that misfolding of peptides and proteins cause the fibrillar aggregates that characterize the group of diseases known as amyloidoses (1, 2). Despite active research, a detailed understanding of the molecular principles underlying the transformation of soluble proteins into amyloid aggregates is still lacking (1-3).The group of peptides and proteins capable of forming amyloid fibrils is very diverse (4-8). This group does not only consist of proteins involved in amyloid deposits in vivo (4), but also of nonpathogenic (15, 16) and designed peptides and proteins (7,8). X-ray fiber diffraction data indicate that all amyloid fibrils share a cross-␤-structure, regardless of the sequence or native fold of the soluble precursor (1, 2). Thus, an increasingly adopted view is that the ability to form amyloid fibrils is a general property of the polypeptide backbone (6). Nevertheless, the propensity of a given polypeptide to form amyloid fibrils depends enormously on amino acid composition (7-10).A protein has to be partially or fully unfolded to aggregate (1, 2). Yet, mutations leading to aggregation can alter (9, 10), or not alter (11, 12), protein stability. Aggregation from some peptides and proteins involved in relevant amyloidoses, such as type II diabetes and Alzheimer's and Parkinson's disease, does not require, however, previous unfolding, because these molecules are largely unstructured under physiological conditions (2). Nevertheless, most of the natively unfolded proteins in vivo do not undergo aggregation (13), indicating that unfolding is necessary, but not sufficient, to promote aggregation. Hence, there must be some sequence motifs tha...

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A Molecular Model of Alzheimer Amyloid β-Peptide Fibril Formation

Cited by 349 publications

References 32 publications

Localization of the noncovalent binding site between amyloid-β-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry

Localization of the noncovalent binding site between amyloid-β-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry

Molecular structure of monomorphic peptide fibrils within a kinetically trapped hydrogel network

Sequence determinants of amyloid fibril formation

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