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Structural convergence among diverse, toxic beta-sheet ion channels.

Jang H, Teran Arce F, Ramachandran S, Capone R, Lal R, Nussinov R - J Phys Chem B (2010)

Bottom Line: However, the intriguing question of preferred channel sizes is still unresolved.Here, exploiting ssNMR-based, U-shaped, beta-strand-turn-beta-strand coordinates, we modeled truncated Abeta peptide (p3) channels with different sizes (12- to 36-mer).Molecular dynamics (MD) simulations show that optimal channel sizes of the ion channels presenting toxic ionic flux range between 16- and 24-mer.

View Article: PubMed Central - PubMed

Affiliation: Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.

ABSTRACT
Recent studies show that an array of beta-sheet peptides, including N-terminally truncated Abeta peptides (Abeta(11-42/17-42)), K3 (a beta(2)-microglobulin fragment), and protegrin-1 (PG-1) peptides form ion channel-like structures and elicit single channel ion conductance when reconstituted in lipid bilayers and induce cell damage through cell calcium overload. Striking similarities are observed in the dimensions of these toxic channels irrespective of their amino acid sequences. However, the intriguing question of preferred channel sizes is still unresolved. Here, exploiting ssNMR-based, U-shaped, beta-strand-turn-beta-strand coordinates, we modeled truncated Abeta peptide (p3) channels with different sizes (12- to 36-mer). Molecular dynamics (MD) simulations show that optimal channel sizes of the ion channels presenting toxic ionic flux range between 16- and 24-mer. This observation is in good agreement with channel dimensions imaged by AFM for Abeta(9-42), K3 fragment, and PG-1 channels and highlights the bilayer-supported preferred toxic beta-channel sizes and organization, regardless of the peptide sequence.

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Related in: MedlinePlus

Cartoons representing the cleavage process by α-, β-, and γ-secretases of the amyloid precursor protein (APP). Various Aβ fragments are processed by different secretase combinations. (a) Amyloidogenic fragments of Aβ1−40/42 are produced by β- and γ-secretase cleavage, and (b) nonamyloidogenic fragments p3 (Aβ17−40/42) are cleaved by α- and γ-secretases.
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fig1: Cartoons representing the cleavage process by α-, β-, and γ-secretases of the amyloid precursor protein (APP). Various Aβ fragments are processed by different secretase combinations. (a) Amyloidogenic fragments of Aβ1−40/42 are produced by β- and γ-secretase cleavage, and (b) nonamyloidogenic fragments p3 (Aβ17−40/42) are cleaved by α- and γ-secretases.

Mentions: In the amyloidogenic pathway, Aβ1−40/42 is produced via cleavage by β- (at position 1) and γ- (position 40 or 42) secretases from the transmembrane amyloid precursor protein (APP) (Figure 1a). Although Aβ1−42 is more toxic to neurons than Aβ1−40, the production of Aβ1−40 is energetically more favorable than the Aβ1−42 formation.(24) In the nonamyloidogenic pathway, APP is processed by β′ and α-secretases to produce Aβ11−40/42 and Aβ17−40/42 (also known as p3), respectively. Due to their putative nonamyloidogenic nature, they are currently pursued as a therapeutic avenue for AD treatment. Current AD drugs targeting the Aβ peptides are designed to block production of the full-length peptides. Those that block the γ-secretase generally lead to side effects, since the γ-secretase also cleaves the transmembrane segment of the Notch protein.(25) Thus, increasingly, drug development efforts target the β-secretase (commonly called BACE) pathway. Yet, drugs that block the β-secretase lead to enhanced production of the N-terminal truncated peptides, such as the Aβ11−42 and similar drugs that stimulate α secretase produce p3 (Figure 1b).(26) Until recently, these truncated Aβ peptides were thought to be nontoxic to neurons. However, recent studies using complementary techniques of molecular dynamics (MD) simulations, atomic force microscopy (AFM), planar lipid bilayer recordings, cell calcium imaging, neuritic degeneration, and cell death assays suggested that nonamyloidogenic p3 and N9 (Aβ9−42) peptides form toxic ion channels.(27) Remarkably, the channel morphology, conductance, and cellular toxicity produced by these truncated Aβ peptides are very similar to those obtained by the full-length Aβ1−40/42 channels.1,14 In addition, since p3 peptides are the major constituent of preamyloid and neuritic plaques in the brain of Down syndrome (DS) patients, p3 channels may also occur in DS.(28)


Structural convergence among diverse, toxic beta-sheet ion channels.

Jang H, Teran Arce F, Ramachandran S, Capone R, Lal R, Nussinov R - J Phys Chem B (2010)

Cartoons representing the cleavage process by α-, β-, and γ-secretases of the amyloid precursor protein (APP). Various Aβ fragments are processed by different secretase combinations. (a) Amyloidogenic fragments of Aβ1−40/42 are produced by β- and γ-secretase cleavage, and (b) nonamyloidogenic fragments p3 (Aβ17−40/42) are cleaved by α- and γ-secretases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2908347&req=5

fig1: Cartoons representing the cleavage process by α-, β-, and γ-secretases of the amyloid precursor protein (APP). Various Aβ fragments are processed by different secretase combinations. (a) Amyloidogenic fragments of Aβ1−40/42 are produced by β- and γ-secretase cleavage, and (b) nonamyloidogenic fragments p3 (Aβ17−40/42) are cleaved by α- and γ-secretases.
Mentions: In the amyloidogenic pathway, Aβ1−40/42 is produced via cleavage by β- (at position 1) and γ- (position 40 or 42) secretases from the transmembrane amyloid precursor protein (APP) (Figure 1a). Although Aβ1−42 is more toxic to neurons than Aβ1−40, the production of Aβ1−40 is energetically more favorable than the Aβ1−42 formation.(24) In the nonamyloidogenic pathway, APP is processed by β′ and α-secretases to produce Aβ11−40/42 and Aβ17−40/42 (also known as p3), respectively. Due to their putative nonamyloidogenic nature, they are currently pursued as a therapeutic avenue for AD treatment. Current AD drugs targeting the Aβ peptides are designed to block production of the full-length peptides. Those that block the γ-secretase generally lead to side effects, since the γ-secretase also cleaves the transmembrane segment of the Notch protein.(25) Thus, increasingly, drug development efforts target the β-secretase (commonly called BACE) pathway. Yet, drugs that block the β-secretase lead to enhanced production of the N-terminal truncated peptides, such as the Aβ11−42 and similar drugs that stimulate α secretase produce p3 (Figure 1b).(26) Until recently, these truncated Aβ peptides were thought to be nontoxic to neurons. However, recent studies using complementary techniques of molecular dynamics (MD) simulations, atomic force microscopy (AFM), planar lipid bilayer recordings, cell calcium imaging, neuritic degeneration, and cell death assays suggested that nonamyloidogenic p3 and N9 (Aβ9−42) peptides form toxic ion channels.(27) Remarkably, the channel morphology, conductance, and cellular toxicity produced by these truncated Aβ peptides are very similar to those obtained by the full-length Aβ1−40/42 channels.1,14 In addition, since p3 peptides are the major constituent of preamyloid and neuritic plaques in the brain of Down syndrome (DS) patients, p3 channels may also occur in DS.(28)

Bottom Line: However, the intriguing question of preferred channel sizes is still unresolved.Here, exploiting ssNMR-based, U-shaped, beta-strand-turn-beta-strand coordinates, we modeled truncated Abeta peptide (p3) channels with different sizes (12- to 36-mer).Molecular dynamics (MD) simulations show that optimal channel sizes of the ion channels presenting toxic ionic flux range between 16- and 24-mer.

View Article: PubMed Central - PubMed

Affiliation: Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.

ABSTRACT
Recent studies show that an array of beta-sheet peptides, including N-terminally truncated Abeta peptides (Abeta(11-42/17-42)), K3 (a beta(2)-microglobulin fragment), and protegrin-1 (PG-1) peptides form ion channel-like structures and elicit single channel ion conductance when reconstituted in lipid bilayers and induce cell damage through cell calcium overload. Striking similarities are observed in the dimensions of these toxic channels irrespective of their amino acid sequences. However, the intriguing question of preferred channel sizes is still unresolved. Here, exploiting ssNMR-based, U-shaped, beta-strand-turn-beta-strand coordinates, we modeled truncated Abeta peptide (p3) channels with different sizes (12- to 36-mer). Molecular dynamics (MD) simulations show that optimal channel sizes of the ion channels presenting toxic ionic flux range between 16- and 24-mer. This observation is in good agreement with channel dimensions imaged by AFM for Abeta(9-42), K3 fragment, and PG-1 channels and highlights the bilayer-supported preferred toxic beta-channel sizes and organization, regardless of the peptide sequence.

Show MeSH
Related in: MedlinePlus