Micropolarities of lipid bilayers and micelles

L'Heureux, G.P.; Fragata, M.

doi:10.1016/0021-9797(87)90412-7

Cited by 22 publications

(5 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The dielectric environment influences the stiffness of amide vibrational modes and pKa differences between donor and acceptor and thus, the chemical rate constants, in an isotope-specific way. The effect will be more pronounced in the low-dielectric interior of the micelle (DK 4–10 64 ) as compared to 80% TFE (DK approx. 35 65 ).…”

Section: Discussionmentioning

confidence: 99%

Increased H-Bond Stability Relates to Altered ε-Cleavage Efficiency and Aβ Levels in the I45T Familial Alzheimer’s Disease Mutant of APP

Götz

Högel

Silber

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Cleavage of the amyloid precursor protein’s (APP) transmembrane domain (TMD) by γ-secretase is a crucial step in the aetiology of Alzheimer’s Disease (AD). Mutations in the APP TMD alter cleavage and lead to familial forms of AD (FAD). The majority of FAD mutations shift the preference of initial cleavage from ε49 to ε48, thus raising the AD-related Aβ42/Aβ40 ratio. The I45T mutation is among the few FAD mutations that do not alter ε-site preference, while it dramatically reduces the efficiency of ε-cleavage. Here, we investigate the impact of the I45T mutation on the backbone dynamics of the substrate TMD. Amide exchange experiments and molecular dynamics simulations in solvent and a lipid bilayer reveal an increased stability of amide hydrogen bonds at the ζ- and γ-cleavage sites. Stiffening of the H-bond network is caused by an additional H-bond between the T45 side chain and the TMD backbone, which alters dynamics within the cleavage domain. In particular, the increased H-bond stability inhibits an upward movement of the ε-sites in the I45T mutant. Thus, an altered presentation of ε-sites to the active site of γ-secretase as a consequence of restricted local flexibility provides a rationale for reduced ε-cleavage efficiency of the I45T mutant.

show abstract

Section: Discussionmentioning

confidence: 99%

Increased H-Bond Stability Relates to Altered ε-Cleavage Efficiency and Aβ Levels in the I45T Familial Alzheimer’s Disease Mutant of APP

Götz

Högel

Silber

et al. 2019

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The dielectric environment influences the stiffness of amide vibrational modes and pKa differences between donor and acceptor and thus, the chemical rate constants, in an isotope-specific way. The effect will be more pronounced in the low-dielectric interior of the micelle (DK 4-10 65 ) as compared to 80% TFE (DK approx. 35 66 ).…”

Section: Discussionmentioning

confidence: 99%

Increased H-Bond Stability Relates to Altered ε-Cleavage Efficiency and Aβ Levels in the I45T Familial Alzheimer’s Disease Mutant of APP

Götz

Högel

Silber

et al. 2018

Preprint

View full text Add to dashboard Cite

1Cleavage of the amyloid precursor protein's (APP) transmembrane domain (TMD) by γ-2 secretase is a crucial step in the etiology of Alzheimer's Disease (AD). Mutations in the APP 3 TMD alter cleavage and lead to familial forms of AD (FAD). The majority of FAD mutations 4 shifts the preference of initial cleavage from ε49 to ε48, thus raising the AD-related Aβ42/Aβ40 5 ratio. The I45T mutation is among the few FAD mutations that do not alter ε-site preference, 6 while it dramatically reduces the efficiency of ε-cleavage. Here we investigate the impact of 7 the I45T mutation on the backbone dynamics of the substrate TMD. Amide exchange 8 experiments and molecular dynamics simulations in solvent and a lipid bilayer reveal an 9 increased stability of amide hydrogen bonds at the ζ-and γ-cleavage sites. Stiffening of the H-10 bond network is caused by an additional H-bond between the T45 side chain and the TMD 11 backbone, which alters dynamics within the cleavage domain. In particular, the increased H-12 bond stability inhibits an upward movement of the ε-sites in the I45T mutant. Thus, an altered 13 presentation of ε-sites to the active site of γ-secretase as a consequence of restricted local 14 flexibility provides a rationale for reduced ε-efficiency of the I45T FAD mutant.15 16 Introduction 1The intramembrane aspartyl protease γ-secretase cleaves the transmembrane domains (TMD) 2 of ~90 bitopic type I transmembrane proteins. 1,2 Due to its involvement in Alzheimer's disease 3 (AD), the amyloid-precursor-protein (APP) is the most extensively studied γ-secretase 4 substrate. 3,4 Prior to cleavage by γ-secretase, APP's ectodomain is shed by β-secretase, thus 5 generating the C99 fragment. Subsequent cleavage of C99 by γ-secretase results in release of 6 the APP intracellular domain (AICD) and β-amyloid (Aβ) peptides of various length. 5 Such 7 step-wise cleavage starts at one of two ε-sites located at the cytosolic border of the C99 TMD 8 between either residue L49 and V50 (ε49) or T48 and L49 (ε48). Cleavage gradually proceeds 9 towards the N-terminus, releasing fragments of three or four residues and leaving Aβ peptides 10 of different length. 6-11 Aβ40, the most abundant Aβ peptide produced from wild-type (WT) 11 C99, is generated by cleavage along the ε49-ζ46-γ43-γ40 pathway. A smaller amount of C99 is 12 processed via cleavage at ε48 and ζ45, leading to Aβ42 and Aβ38 peptides. Of these species, 13Aβ42 is the most aggregation-prone and forms neurotoxic oligomers and plaques. 12,13 The 14 accumulation of plagues consisting of such cell-toxic Aβ peptides in the brain is a central 15 hallmark of AD. 14 In familial forms of AD (FAD) an increased Aβ42/Aβ40 ratio correlates with 16 early onset and fast progression of AD and results from point mutations in C99 or presenilin, 17 the catalytic subunit of γ-secretase. 1,[15][16][17][18][19][20][21] In most mutants, alterations in Aβ42/Aβ40 ratios are 18 linked to shifting the preferential initial cleavage site from ε49 to ε48. However, switching of 19 pathways after ε-cl...

show abstract

“…The vibronic band intensities of the monomer spectrum exhibit a dependence on the solvent polarity . Consequently, the ratio of monomer emission bands I (λ ∼ 373 nm) and III (λ ∼ 384 nm) have been used to determine the local polarity of many media. , Excited pyrene monomers also form excimers in concentrated solution. The excimer spectrum is substantially red-shifted relative to the monomer spectrum, and the ratio of monomer emission bands (λ ∼ 400 nm) to excimer emission bands (λ ∼ 470 nm) has been used as an indicator of concentration dependent medium properties. − Pyrene has a very long intrinsic fluorescence lifetime which leads to a decay rate that is particularly sensitive to the local environment of the probe.…”

Section: Introductionmentioning

confidence: 99%

“…1 Consequently, the ratio of monomer emission bands I (λ ∼ 373 nm) and III (λ ∼ 384 nm) have been used to determine the local polarity of many media. 2,3 Excited pyrene monomers also form excimers in concentrated solution. The excimer spectrum is substantially red-shifted relative to the monomer spectrum, and the ratio of monomer emission bands (λ ∼ 400 nm) to excimer emission bands (λ ∼ 470 nm) has been used as an indicator of concentration dependent medium properties.…”

Section: Introductionmentioning

confidence: 99%

Model-Independent Analysis of Pyrene Photokinetics in SDS Micelles

Villegas

Neal

1997

J. Phys. Chem. A

View full text Add to dashboard Cite

In this report, the dependence of pyrene photokinetics on sodium dodecyl sulfate (SDS) micelle concentration is investigated Via dynamic multidimensional fluorescence measurements. First, complex quantum yield matrices were constructed from steady-state spectra and multiple wavelength phase/modulation data. These matrices were then subjected to rank analysis in order to determine the number of spectrally distinct pyrene components. The consensus of these results is that there are three spectrally distinguishable pyrene components. Then, the emission spectra of the pyrene components, their relative initial concentrations, and the photokinetic transfer matrix, which describes their decay and interaction, are estimated without model assumptions. The characteristics of the fluorescence spectra and their dependence on the SDS concentration identify the three components as pyrene excimer, aggregates, and monomers. The results also indicate that pyrene decay kinetics in SDS micelles vary substantially with the SDS concentration. At low surfactant concentration, pyrene decays Via an irreversible 3-state mechanism. As the surfactant concentration is increased, the rate of the rate of the excimer dissociation reaction increases and the mechanism becomes reversible.

show abstract

Micropolarities of lipid bilayers and micelles

Cited by 22 publications

References 52 publications

Increased H-Bond Stability Relates to Altered ε-Cleavage Efficiency and Aβ Levels in the I45T Familial Alzheimer’s Disease Mutant of APP

Increased H-Bond Stability Relates to Altered ε-Cleavage Efficiency and Aβ Levels in the I45T Familial Alzheimer’s Disease Mutant of APP

Increased H-Bond Stability Relates to Altered ε-Cleavage Efficiency and Aβ Levels in the I45T Familial Alzheimer’s Disease Mutant of APP

Model-Independent Analysis of Pyrene Photokinetics in SDS Micelles

Contact Info

Product

Resources

About