Amyloid fibrillogenesis: themes and variations

Rochet, Jean‐Christophe; Lansbury, Peter T.

doi:10.1016/s0959-440x(99)00049-4

Cited by 1,043 publications

(958 citation statements)

References 76 publications

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“…All forces are modeled by either a hard-sphere potential: (1) where r is the distance between spheres i and j and σ is the sphere diameter, or a square-well potential (2) where λσ is the well diameter and ε is the well depth. The excluded volumes of the four united atoms are modeled using hard-sphere potentials with realistic diameters.…”

Section: Model Peptide and Forcesmentioning

confidence: 99%

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Nguyen

Hall

2006

J. Am. Chem. Soc.

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Fibrillary protein aggregates rich in β-sheet structure have been implicated in the pathology of several neurodegenerative diseases. In this work, we investigate the formation of fibrils by performing discontinuous molecular dynamics simulations on systems containing 12 to 96 model Ac-KA 14 K-NH 2 peptides using our newly-developed off-lattice, implicit-solvent, intermediateresolution model, PRIME. We find that at a low concentration, random-coil peptides assemble into α-helices at low temperatures. At intermediate concentrations, random-coil peptides assemble into α-helices at low temperatures and large β-sheet structures at high temperatures. At high concentrations, the system forms β-sheets over a wide range of temperatures. These assemble into fibrils above a critical temperature which decreases with concentration and exceeds the isolated peptide's folding temperature. At very high temperatures and all concentrations, the system is in a random-coil state. All of these results are in good qualitative agreement with those by Blondelle and coworkers on Ac-KA 14 K-NH 2 peptides. The fibrils observed in our simulations mimic the structural characteristics observed in experiments in terms of the number of sheets formed, the values of the intra-and inter-sheet separations, and the parallel peptide arrangement within each β-sheet. Finally, we find that when the strength of the hydrophobic interaction between non-polar sidechains is high compared to the strength of hydrogen bonding, amorphous aggregates, rather than fibrillar aggregates, are formed.

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Section: Model Peptide and Forcesmentioning

confidence: 99%

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Nguyen

Hall

2006

J. Am. Chem. Soc.

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“…9 In Alzheimer's disease, Ab bers deposit in the extracellular space of the brain and on walls of cerebral blood vessels as amyloid plaques. 10 In the last decade, it was recognized that prebrillar assemblies actually represent the toxic elements responsible for cell death in the infected tissues. 11 The species isolated at the early stages of aggregation were characterized as protobrillar aggregates, comprised of stacks usually formed by two to four b-sheet tapes, 20-70 nm in length and 3 nm in diameter.…”

Section: Introductionmentioning

confidence: 99%

A single-residue substitution inhibits fibrillization of Ala-based pentapeptides. A spectroscopic and molecular dynamics investigation

et al. 2014

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The aggregation properties of two Ala-based pentapeptides were investigated by spectroscopic techniques and molecular dynamics (MD) simulations. The two peptides, both functionalized at the N-terminus with a pyrenyl group, differ in the insertion of an a-aminoisobutyric acid residue at position 4. We showed that this single modification of the homo-peptide sequence inhibits the aggregation of the pentapeptide in aqueous solutions. Atomic force microscopy imaging revealed that the two peptides form mesoscopic aggregates of very different morphologies when deposited on mica. MD experiments showed that the two peptides have a very different propensity to form b-pleated sheet structures, as confirmed by our spectroscopic measurements. The implications of these findings for our understanding of the mechanism leading to the formation of amyloid structures, primary responsible for numerous neurodegenerative diseases, are also discussed.

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“…Many age-related diseases (including Alzheimer's disease, the transthyretin amyloidoses, Parkinson's disease, Huntington's disease, and familial amyloidosis of Finnish type) are associated with amyloidogenesis, a process by which proteins misassemble or misfold and misassemble into both soluble and insoluble cross-b-sheet fibrillar aggregates called amyloid. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Amyloid is toxic when applied exogenously to or when formed within cultured cells. [19][20][21][22][23][24][25][26][27][28][29][30][31][32] Mouse and C. elegans models of amyloid diseases show that the cytotoxicity associated with amyloidogenesis increases with organismal age.…”

Section: Introductionmentioning

confidence: 99%

“…Identifying the molecular machinery responsible for the mammalian disaggregase activity and, ultimately, adapting this machinery offer the prospect of ameliorating age-related degenerative diseases in which cytotoxicity is genetically linked to the process of amyloidogenesis. 5,[10][11][12][13][14][15][16][17][18][19]22,30,[33][34][35][36][37] Results…”

Section: Introductionmentioning

confidence: 99%

Discovery and characterization of a mammalian amyloid disaggregation activity

Murray¹,

Solomon²,

Wang³

et al. 2010

Protein Science

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The formation of amyloid, a cross-b-sheet fibrillar aggregate, is associated with a variety of aging-associated degenerative diseases. Herein, we report the existence of a mammalian amyloid disaggregase activity that is present in all tissues and cell types tested. Homogenates from mammalian tissues and cell lines are able to disaggregate amyloid fibrils composed of amyloid b (Ab) 1-40 or the 8 kDa plasma gelsolin fragment. The mammalian disaggregase activity is sensitive to proteinase K digestion and can be uncoupled from proteolysis activity using a protease inhibitor cocktail. Amyloid disaggregation and proteolysis activities are remarkably resistant to changes in temperature and pH. Identification and manipulation of the proteins responsible for the amyloid disaggregation/degradation activities offers the possibility of ameliorating aggregation-associated diseases.

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Amyloid fibrillogenesis: themes and variations

Cited by 1,043 publications

References 76 publications

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

A single-residue substitution inhibits fibrillization of Ala-based pentapeptides. A spectroscopic and molecular dynamics investigation

Discovery and characterization of a mammalian amyloid disaggregation activity

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