New structures help the modeling of toxic amyloidß ion channels

Jang, Hyunbum; Zheng, Jie; Lal, Ratnesh; Nussinov, Ruth

doi:10.1016/j.tibs.2007.10.007

Cited by 138 publications

(223 citation statements)

References 72 publications

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“…Consistent with earlier observations (5,25), the channel outer β-sheet, absent in the initial structure because of the larger curvature at the channel periphery, is recovered at certain regions and the channel organizes into several small subunits with or without disordered monomers in between ( Fig. 1 A and B).…”

Section: Resultssupporting

confidence: 91%

“…3G) and p3 (Fig. 3H) channel structures confirm that cations are easily trapped by the negatively charged Glu22 side-chains at the top bilayer leaflet, creating a cationic ring (5,25). In the p3 pore (Fig.…”

Section: Resultsmentioning

confidence: 77%

“…Early MD simulations of amyloidogenic peptides (5,25) consisting of U-shaped β-strandturn-β-strand peptides in the bilayer predicted ion-permeable channels formed by loosely attached mobile subunits with morphologies and dimensions similar to the AFM-images of amyloid channels (7,8). U-shaped motifs, first predicted by modeling of Aβ [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] (26), appear as a general feature of amyloid organization, suggesting that other U-shaped amyloid organizations may also form dynamic ion channels in the fluidic membrane (8).…”

Section: Resultsmentioning

confidence: 99%

“…U-shaped motifs, first predicted by modeling of Aβ [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] (26), appear as a general feature of amyloid organization, suggesting that other U-shaped amyloid organizations may also form dynamic ion channels in the fluidic membrane (8). Because N9 and p3 have membrane-spanning segments, we modeled their 3D structures in the bilayer using the previous successful protocol (5,25). Using the two available Aβ oligomer coordinate sets (27,28), we constructed annular channels based on the U-shaped β-strand-turn-β-strand motif.…”

Section: Resultsmentioning

confidence: 99%

“…Aβ 1-40/42 peptides form β-sheet-rich ordered aggregates and soluble oligomers. Small oligomers are emerging as the predominant toxic species (1-3); the toxicity is believed to be a result of the loss of ionic homeostasis, presumably via ion channels formed in cellular membranes (4,5). EM images of Aβ oligomers show doughnut-like morphologies (6).…”

mentioning

confidence: 99%

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Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Jang

Arce

Ramachandran

et al. 2010

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

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Full-length amyloid beta peptides (Aβ 1-40/42 ) form neuritic amyloid plaques in Alzheimer's disease (AD) patients and are implicated in AD pathology. However, recent transgenic animal models cast doubt on their direct role in AD pathology. Nonamyloidogenic truncated amyloid-beta fragments and Aβ ) are also found in amyloid plaques of AD and in the preamyloid lesions of Down syndrome, a model system for early-onset AD study. Very little is known about the structure and activity of these smaller peptides, although they could be the primary AD and Down syndrome pathological agents. Using complementary techniques of molecular dynamics simulations, atomic force microscopy, channel conductance measurements, calcium imaging, neuritic degeneration, and cell death assays, we show that nonamyloidogenic Aβ 9-42 and Aβ 17-42 peptides form ion channels with loosely attached subunits and elicit single-channel conductances. The subunits appear mobile, suggesting insertion of small oligomers, followed by dynamic channel assembly and dissociation. These channels allow calcium uptake in amyloid precursor protein-deficient cells. The channel mediated calcium uptake induces neurite degeneration in human cortical neurons. Channel conductance, calcium uptake, and neurite degeneration are selectively inhibited by zinc, a blocker of amyloid ion channel activity. Thus, truncated Aβ fragments could account for undefined roles played by full length Aβs and provide a unique mechanism of AD and Down syndrome pathologies. The toxicity of nonamyloidogenic peptides via an ion channel mechanism necessitates a reevaluation of the current therapeutic approaches targeting the nonamyloidogenic pathway as avenue for AD treatment.atomic force microscopy | molecular dynamics | cell calcium imaging | neurite degeneration and cell death assays | single-channel conductance A myloid-beta peptides (Aβ 1-40/42 ) produced by β-and γ-secretase processing of amyloid precursor protein (APP) in the amyloidogenic pathway are involved in Alzheimer's disease (AD) pathology. Aβ 1-40/42 peptides form β-sheet-rich ordered aggregates and soluble oligomers. Small oligomers are emerging as the predominant toxic species (1-3); the toxicity is believed to be a result of the loss of ionic homeostasis, presumably via ion channels formed in cellular membranes (4, 5). EM images of Aβ oligomers show doughnut-like morphologies (6). Atomic force microscopic (AFM) images of Aβ peptides reconstituted in lipid bilayers show heteromeric (rectangular to hexagonal) ion channel-like structures with a ∼2.0-nm central pore and 8-to 12-nm outer diameters (7,8). Electrophysiological studies show heterodisperse cationselective single-channel conductances (7)(8)(9)(10)(11)(12)(13)(14) that are consistent with features of other amyloid ion channels (6-8).On the other hand, when APP is cleaved by γ-and α-secretases, it forms the nonamyloidogenic pathway generating ∼2.6-kDa fragments (Aβ 17-40/42 ) known as the p3 peptides (15). Cleavage by γ and BACE between Tyr10 and Glu11 generates another...

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Jang

Arce

Ramachandran

et al. 2010

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

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210

333

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Ion Channels: Computational Analysis

Kurnikova

2008

Wiley Encyclopedia of Chemical Biology

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Ion channels are proteins that are embedded in the lipid bilayer and open water filled pores for ion conduction. This article briefly discusses applications of the methods of computational chemistry to model structure and properties of ion channels. Molecular dynamics simulations are applied to study structure–function relationships in ion channels, their interaction with the lipid bilayer, as well as some aspects of gating and selectivity. Ion permeation properties of the channels are typically modeled using coarse‐grained theories based on continuum representation of water, protein and sometimes permeating ions. In such models, interaction of ions with the environment is governed by the Poisson equation of classic electrostatics. Dynamic flow of ions is modeled by using either Brownian Dynamics (BD) [or alternatively Dynamic Monte Carlo methods (DMC)] or by using continuum diffusion formalism. A model that combines continuum diffusion formalism with the Poisson equation is termed Poisson–Nernst–Planck (PNP) theory. A generalized continuum flow theory that accounts for a single ion interaction with the environment is termed Potential of Mean Force PMP (PMFPNP). The main limitation of both BD and PNP theories stems from the rigid representation of the protein and the membrane. In many hybrid models, this limitation has been overcome.

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Wechselwirkungen zwischen amyloidogenen Proteinen und Membranen: Modellsysteme liefern mechanistische Einblicke

Butterfield

Lashuel

2010

Angewandte Chemie

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Die Toxizität amyloidbildender Proteine ist mit ihrer Wechselwirkung mit Membranen korreliert. Bemerkenswerterweise führen Bindungsereignisse zwischen amyloidogenen Proteinen und Membranen beiderseits zu Strukturstörungen, die mit Toxizität assoziiert sind. Membranoberflächen vermitteln die Umwandlung amyloidbildender Proteine in toxische Aggregate, amyloidbildende Proteine wiederum beeinträchtigen die strukturelle Integrität der Zellmembran. Neuere Untersuchungen an künstlichen Modellmembranen haben eine bemerkenswerte Ähnlichkeit im Mechanismus der Membranpermeabilisierung von amyloidbildenden Proteinen, porenbildenden Toxinen und antimikrobiellen Peptiden aufgezeigt.

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New structures help the modeling of toxic amyloidß ion channels

Cited by 138 publications

References 72 publications

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Ion Channels: Computational Analysis

Wechselwirkungen zwischen amyloidogenen Proteinen und Membranen: Modellsysteme liefern mechanistische Einblicke

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