Ten to fourteen residue peptides of Alzheimer's disease protein are sufficient for amyloid fibril formation and its characteristic xray diffraction pattern

Gorevic, P. D.; Castaño, E. M.; Sarma, Raghupathy; Frangione, Blas

doi:10.1016/0006-291x(87)91008-4

Cited by 162 publications

(121 citation statements)

References 20 publications

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“…The process thus resembles proteins that precipitate transiently en route to forming crystals, and experimental support for a link between fibrillation and protein crystallization was recently reported by atomic force microscopy studies (34). Together with the evidence of multiple interaction registers from ␤-AP fragments (6,9,35), it seems reasonable to assume that variations in aggregate morphologies stem from alternative registers within a common ␤-packing. In the case of S6, however, the aggregation process is terminated at an early stage: the drive to fold rips the primary aggregates apart.…”

Section: A Link Between Tetramerization Transient Aggregation and Pmentioning

confidence: 68%

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Designed protein tetramer zipped together with a hydrophobic Alzheimer homology: A structural clue to amyloid assembly

Otzen

Kristensen

Oliveberg

2000

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

177

147

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Limited solubility and precipitation of amyloidogenic sequences such as the Alzheimer peptide (␤-AP) are major obstacles to a molecular understanding of protein fibrillation and deposition processes. Here we have circumvented the solubility problem by stepwise engineering a ␤-AP homology into a soluble scaffold, the monomeric protein S6. The S6 construct with the highest ␤-AP homology crystallizes as a tetramer that is linked by the ␤-AP residues forming intermolecular antiparallel ␤-sheets. This construct also shows increased coil aggregation during refolding, and a 14-mer peptide encompassing the engineered sequence forms fibrils. Mutational analysis shows that intermolecular association is linked to the overall hydrophobicity of the sticky sequence and implies the existence of ''structural gatekeepers'' in the wild-type protein, that is, charged side chains that prevent aggregation by interrupting contiguous stretches of hydrophobic residues in the primary sequence.

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Section: A Link Between Tetramerization Transient Aggregation and Pmentioning

confidence: 68%

“…Fragments of residues 18-28 assemble into ribbon-like structures (9), whereas fragments involving the hydrophobic C terminus may assume a fully extended filament structure (6). The assemblies are further sensitive to mutagenesis.…”

mentioning

confidence: 99%

Designed protein tetramer zipped together with a hydrophobic Alzheimer homology: A structural clue to amyloid assembly

Otzen

Kristensen

Oliveberg

2000

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

177

147

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“…Membrane-associated mechanisms of A␤ neurotoxicity include membrane depolarization (36,37), membrane destabilization (46 -48), pore formation (66 -69), and membrane-associated free radical generation (70 -73). A membrane-mediated step could also be associated with the observed A␤-induced alterations in intracellular signaling (74 -76), ion channel function (77)(78)(79)(80), and calcium homeostasis (81)(82)(83)(84).…”

Section: Discussionmentioning

confidence: 99%

Reduction in Cholesterol and Sialic Acid Content Protects Cells from the Toxic Effects of β-Amyloid Peptides

Wang

Rymer

Good

2001

Journal of Biological Chemistry

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␤-Amyloid (A␤) is the primary protein component of senile plaques associated with Alzheimer's disease and has been implicated in the neurotoxicity associated with the disease. A variety of evidence points to the importance of A␤-membrane interactions in the mechanism of A␤ neurotoxicity and indicates that cholesterol and gangliosides are particularly important for A␤ aggregation and binding to membranes. We investigated the effects of cholesterol and sialic acid depletion on A␤-induced GTPase activity in cells, a step implicated in the mechanism of A␤ toxicity, and A␤-induced cell toxicity. Cholesterol reduction and depletion of membraneassociated sialic acid residues both significantly reduced the A␤-induced GTPase activity. In addition, cholesterol and membrane-associated sialic acid residue depletion or inhibition of cholesterol and ganglioside synthesis protected PC12 cells from A␤-induced toxicity. These results indicate the importance of A␤-membrane interactions in the mechanism of A␤ toxicity. In addition, these results suggest that control of cellular cholesterol and/or ganglioside content may prove useful in the prevention or treatment of Alzheimer's disease.An important pathological hallmark of Alzheimer's disease (AD) 1 is the formation and progressive deposition of insoluble amyloid fibrils within the cerebral cortex (1). The key constituent of these amyloid deposits has been identified as a 39 -43-amino acid long polypeptide, ␤-amyloid peptide (A␤), which is derived primarily from the proteolytic cleavage of a much larger amyloid precursor protein (2). Presenilin 1 and 2 are believed to be involved in the proteolytic processing of the A␤ fragment (3-6). Evidence for the causative role of A␤ in the pathogenesis of AD partly comes from genetic studies, which linked mutations in the amyloid precursor protein and in the presenilins to inheritable forms of AD (7-9). Further evidence originates from in vitro toxicity studies with synthetic A␤ peptides, which have shown that A␤, in an aggregated state (fibril, protofibril, low molecular weight oligomer, or diffusible, nonfibrillar ligand), is toxic to neurons in culture (10 -17). Although it seems certain that A␤ plays a role in neurotoxicity associated with AD, the molecular mechanism of A␤ neurotoxicity remains unclear.Increasing evidence indicates that the neuronal cell membrane is important in the mechanism of A␤ toxicity. Studies (18 -21) have indicated that membrane components such as cholesterol and gangliosides alter the affinity of A␤ for phospholipid membranes. Once associated with the membranes, negatively charged phospholipids, cholesterol, and gangliosides have been shown to increase the ␤-sheet content and/or rate of aggregation of A␤ (19,(21)(22)(23)(24). Both in vivo and in vitro, alterations in soluble cholesterol and/or cholesterol biosynthesis have also been shown to affect the normal processing of amyloid precursor protein (25)(26)(27). In these studies, the inhibition of cholesterol synthesis led to decreased A␤ formation (25,27). In...

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“…Previously, two groups (Gorevic et al, 1987;Kirschner et al, 1987) raised the possibility of a turn encompassing residues Asp7-Tyrl0. Zagorski and Barrow (1992) have since ruled out the presence of such a turn based on the absence of a number of sequential and medium-range NOEs in this segment in their CF,CD,OD/H,O study.…”

Section: Secondary Structure Analysis Of the Native And Mutant Fragmentsmentioning

confidence: 99%

“…The partially membrane-bound protein precluded the possibility of studying the whole PA4 sequence since it would be a difficult task to mimic NMR solvent conditions whereby part of the peptidelprotein under study is in an 'extracellular' environment and the other part in a 'membrane' environment. Due to these limitations, we are studying synthetic extracellular fragments of PA4 which have demonstrated in vitro formation of aniyloid fibrils under physiological conditions (Castano et al, 1986;Gorevic et al, 1987;., 1987). The NMR data is then combined with computational techniques to generate possible three-dimensional structures and to assist in the understanding of local or long-range interactions.…”

mentioning

confidence: 99%

Structure determination of extracellular fragments of amyloid proteins involved in Alzheimer's disease and Dutch‐type hereditary cerebral haemorrhage with amyloidosis

Sorimachi

Craik

1994

European Journal of Biochemistry

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Amyloid deposition is a biochemical and histopathologic hallmark of various clinical forms of amyloidoses including Alzheimer's disease and the Dutch‐type hereditary cerebral haemorrhage with amyloidosis. The self‐aggregating peptides responsible for these irreversible deposits have been sequenced but the mechanisms involved in the aggregation processes are not well understood. In order to gain an understanding of the possible structures prior to self‐association, the extracellular fragment of the Alzheimer amyloid protein (βA4) responsible for the deposits (the ‘native’ fragment) and a mutant of this with a single residue substitution (which is responsible for deposits in the Dutch‐type amyloidosis) were examined by 1H‐NMR spectroscopy. Interproton distance constraints were derived from NMR experimental data and incorporated into tertiary structure calculations using a simulated annealing protocol. Solution conformations of the fragment peptides associated with the two forms of amyloidoses are presented and compared. Although in both peptides the existence of a mixture of conformations in equilibrium is likely, one such population of structures possesses a flexible N‐terminus and a well defined C‐terminal region. The latter region includes a helical segment and a terminal turn‐like structure. These structural features may be important for the basis of amyloid formation. Comparison of the calculated structures of the two peptides revealed a conformationally different region arising from the conservative substitution of Gln22 for Glu22. This region may be responsible for altered binding in the mutant peptide, giving rise to the clinically different form of amyloidosis.

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Ten to fourteen residue peptides of Alzheimer's disease protein are sufficient for amyloid fibril formation and its characteristic xray diffraction pattern

Cited by 162 publications

References 20 publications

Designed protein tetramer zipped together with a hydrophobic Alzheimer homology: A structural clue to amyloid assembly

Designed protein tetramer zipped together with a hydrophobic Alzheimer homology: A structural clue to amyloid assembly

Reduction in Cholesterol and Sialic Acid Content Protects Cells from the Toxic Effects of β-Amyloid Peptides

Structure determination of extracellular fragments of amyloid proteins involved in Alzheimer's disease and Dutch‐type hereditary cerebral haemorrhage with amyloidosis

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