On the helix sense of gramicidin A single channels

Koeppe, Roger E.; Providence, Lyndon L.; Greathouse, Denise V.; Heitz, Fréderic; Trudelle, Y.; Purdie, Neil; Andersen, Olaf S.

doi:10.1002/prot.340120107

Cited by 62 publications

(67 citation statements)

References 49 publications

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“…For proteins, the orientation of individual amide bonds is responsible for the resulting CD spectra in the far-UV region. Mirror image structures, formed by replacing whole L-amino acid sequences with D-amino acids, such as gramicidin A, produce mirror-image CD-spectra (Koeppe et al, 1992). We anticipate that the α-sheet structure would be effectively invisible due to near equal absorbance of both left and right polarized light, with any residual signal emanating from the turns and terminal residues.…”

Section: Resultsmentioning

confidence: 99%

Designed α-sheet peptides inhibit amyloid formation by targeting toxic oligomers

Hopping

Kellock

Barnwal

et al. 2014

eLife

119

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Previous studies suggest that the toxic soluble-oligomeric form of different amyloid proteins share a common backbone conformation, but the amorphous nature of this oligomer prevents its structural characterization by experiment. Based on molecular dynamics simulations we proposed that toxic intermediates of different amyloid proteins adopt a common, nonstandard secondary structure, called α-sheet. Here we report the experimental characterization of peptides designed to be complementary to the α-sheet conformation observed in the simulations. We demonstrate inhibition of aggregation in two different amyloid systems, β-amyloid peptide (Aβ) and transthyretin, by these designed α-sheet peptides. When immobilized the α-sheet designs preferentially bind species from solutions enriched in the toxic conformer compared with non-aggregated, nontoxic species or mature fibrils. The designs display characteristic spectroscopic signatures distinguishing them from conventional secondary structures, supporting α-sheet as a structure involved in the toxic oligomer stage of amyloid formation and paving the way for novel therapeutics and diagnostics.DOI: http://dx.doi.org/10.7554/eLife.01681.001

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Section: Resultsmentioning

confidence: 99%

Designed α-sheet peptides inhibit amyloid formation by targeting toxic oligomers

Hopping

Kellock

Barnwal

et al. 2014

eLife

119

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“…If the backbone structure of [Ala',~-Ala~]-gA were dramatically perturbed, hybrid channels would not form (Durkin et al, 1992;Koeppe et al, 1992). As illustrated in Figure 8, hybrid channels form between [Ala',DAla2]gA and [Val',Gly2]gA, as evidenced by the presence of a new channel type when the two gramicidins are present together.…”

Section: Heterodimer Experimentsmentioning

confidence: 92%

Stabilizing Effect of D-Alanine2 in Gramicidin Channels

Mattice¹,

Koeppe²,

Providence³

et al. 1995

Biochemistry

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We have investigated the effects of replacing Gly2 by D-Ala2 in gramicidin A (gA) analogues that have either L-Val, L-Ala, or Gly as the formyl-N-terminal residue. Circular dichroism, two-dimensional nuclear magnetic resonance, and hybrid channel experiments all show that [Ala1,D-Ala2]gA channels are structurally equivalent to the native [Val1,Gly2]gA channels, being formyl-NH-to-formyl-NH dimers of single-stranded, right-handed beta 6.3 helices. Replacing the Val1 of gA by Ala or Gly decreases the average channel duration. Replacing Gly2 by D-Ala in [Val1,Gly2]gA increases the average channel duration 4-fold and the single-channel conductance by approximately 15%; replacing Gly2 with D-Ala in [Ala1,Gly2]gA or [Gly1,Gly2]-gA leads in each case to a 10-fold increase in the average channel duration with only modest changes in the single-channel conductance, which depends on the identity of the position-one residue and the permeant ion. These results illustrate the importance of neighboring-residue side chain and backbone interactions for the modulation of channel properties.

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“…But the presence of the acyl chain could alter the normal folding and, for example, change the helix sense from right-handed (Arseniev et al, 1985(Arseniev et al, , 1986Nicholson et al, 1989;Koeppe et al, 1992) to left-handed. The ethanolamine moiety has in fact been implicated as being important for normal function (Etchebest & Pullman, , 1986.…”

Section: Nh-terminal)-to-(formyl-nh-terminal) $3-helical Dimersmentioning

confidence: 99%

Molecular and channel-forming characteristics of gramicidin K's: a family of naturally occurring acylated gramicidins

WILLIAMS

Narcessian²,

Andersen³

et al. 1992

Biochemistry

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The gramicidin K family is a set of naturally occurring acylated linear peptides in which a fatty acid is esterified to the ethanolamine hydroxyl of either gramicidin A or C, and possibly also to gramicidin B (Koeppe, R. E., II, Paczkowski, J. A., & Whaley, W. L. (1985) Biochemistry 24, 2822-2826). These acylated gramicidins form membrane-spanning channels in planar lipid bilayers and therefore constitute a model system with which to study the structural and functional consequences of acylation on membrane proteins. This paper serves to characterize further the channels formed by acylated gramicidins A and C and to demonstrate that these channels are structurally equivalent to the channels formed by the standard gramicidins. We also present additional evidence for the ester linkage in the natural acylated gramicidins A and C and identify the fatty acyl chains.

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On the helix sense of gramicidin A single channels

Cited by 62 publications

References 49 publications

Designed α-sheet peptides inhibit amyloid formation by targeting toxic oligomers

Designed α-sheet peptides inhibit amyloid formation by targeting toxic oligomers

Stabilizing Effect of D-Alanine2 in Gramicidin Channels

Molecular and channel-forming characteristics of gramicidin K's: a family of naturally occurring acylated gramicidins

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