A folding transition underlies the emergence of membrane affinity in amyloid-β

Nag, Suman; Sarkar, Bidyut; Chandrakesan, Muralidharan; Abhyanakar, Rajiv; Bhowmik, Debanjan; Kombrabail, Mamata; Dandekar, Sucheta; Lerner, Eitan; Haas, Elisha; Maiti, Sudipta

doi:10.1039/c3cp52732h

Cited by 37 publications

(43 citation statements)

References 38 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous simulation studies on beta-sheet-rich beta-amyloid p3 dimer (Jang et al, 2013) on mono-unsaturated PC surfaces and beta-amyloid pentamer (Tofoleanu et al, 2015) on all-unsaturated PC surfaces have also reported spontaneous unfolding of beta-sheets, and therefore agree with our results. Previous studies (McLaurin and Chakrabartty, 1997; Wong et al, 2009; Nag et al, 2013) have revealed that the presence of anionic lipid supports and promotes beta-sheet structures on membrane surfaces. However, in our study, the anionic PS lipids in the PC/PS asymmetric bilayer were not in contact with the protein.…”

Section: Discussionmentioning

confidence: 99%

Maximally asymmetric transbilayer distribution of anionic lipids alters the structure and interaction with lipids of an amyloidogenic protein dimer bound to the membrane surface

Cheng

Chou

Buie

et al. 2016

Chemistry and Physics of Lipids

View full text Add to dashboard Cite

We used molecular dynamics simulations to explore the effects of asymmetric transbilayer distribution of anionic phosphatidylserine (PS) lipids on the structure of a protein on the membrane surface and subsequent protein–lipid interactions. Our simulation systems consisted of an amyloidogenic, beta-sheet rich dimeric protein (D42) absorbed to the phosphatidylcholine (PC) leaflet, or protein-contact PC leaflet, of two membrane systems: a single-component PC bilayer and double PC/PS bilayers. The latter comprised of a stable but asymmetric transbilayer distribution of PS in the presence of counterions, with a 1-component PC leaflet coupled to a 1-component PS leaflet in each bilayer. The maximally asymmetric PC/PS bilayer had a non-zero transmembrane potential (TMP) difference and higher lipid order packing, whereas the symmetric PC bilayer had a zero TMP difference and lower lipid order packing under physiologically relevant conditions. Analysis of the adsorbed protein structures revealed weaker protein binding, more folding in the N-terminal domain, more aggregation of the N- and C-terminal domains and larger tilt angle of D42 on the PC leaflet surface of the PC/PS bilayer versus the PC bilayer. Also, analysis of protein-induced membrane structural disruption revealed more localized bilayer thinning in the PC/PS versus PC bilayer. Although the electric field profile in the non-protein-contact PS leaflet of the PC/PS bilayer differed significantly from that in the non-protein-contact PC leaflet of the PC bilayer, no significant difference in the electric field profile in the protein-contact PC leaflet of either bilayer was evident. We speculate that lipid packing has a larger effect on the surface adsorbed protein structure than the electric field for a maximally asymmetric PC/PS bilayer. Our results support the mechanism that the higher lipid packing in a lipid leaflet promotes stronger protein–protein but weaker protein–lipid interactions for a dimeric protein on membrane surfaces.

show abstract

Section: Discussionmentioning

confidence: 99%

Maximally asymmetric transbilayer distribution of anionic lipids alters the structure and interaction with lipids of an amyloidogenic protein dimer bound to the membrane surface

Cheng

Chou

Buie

et al. 2016

Chemistry and Physics of Lipids

View full text Add to dashboard Cite

show abstract

“…(263,270) Total internal reflection fluorescence microscopy (TIRFM) enables the visualization of individual Aβ species on membranes and the characterization of their oligomeric states, all at biologically relevant nanomolar concentrations. (58b,280,281) …”

Section: Interactions Of Aβ Peptides With Membranesmentioning

confidence: 99%

Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Aggregates were then resuspended in appropriate amount of phosphate buffer, so that all vortexed solutions had similar tyrosine fluorescence (which ensures matching final peptide concentrations). 10 l of ice-cold H 2 O 2 and 6 l of freshly prepared FeSO 4 were added simultaneously to 600 l of these peptide solutions. These solutions were then vortexed for 60 s. Fluorescence spectra were obtained immediately by exciting at 260 nm.…”

Section: Methodsmentioning

confidence: 99%

“…In this process, the unstructured monomers of A␤ get converted into amyloid fibrils composed of hairpin-shaped monomeric units assembled in a parallel ␤ sheet arrangement (3,4). The central part of this hairpin structure consists of a hydrophilic region flanked by hydrophobic ␤-sheet-forming segments at both ends (5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Steric Crowding of the Turn Region Alters the Tertiary Fold of Amyloid-β18–35 and Makes It Soluble

Chandrakesan

Bhowmik

Sarkar

et al. 2015

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

A␤ self-assembles into parallel cross-␤ fibrillar aggregates, which is associated with Alzheimer's disease pathology. A central hairpin turn around residues 23-29 is a defining characteristic of A␤ in its aggregated state. Major biophysical properties of A␤, including this turn, remain unaltered in the central fragment A␤ 18 -35 . Here, we synthesize a single deletion mutant, ⌬G25, with the aim of sterically hindering the hairpin turn in A␤ 18 -35 . We find that the solubility of the peptide goes up by more than 20-fold. Although some oligomeric structures do form, solution state NMR spectroscopy shows that they have mostly random coil conformations. Fibrils ultimately form at a much higher concentration but have widths approximately twice that of A␤ 18 -35 , suggesting an opening of the hairpin bend. Surprisingly, two-dimensional solid state NMR shows that the contact between Phe 19 and Leu 34 residues, observed in full-length A␤ and A␤ 18 -35 , is still intact in these fibrils. This is possible if the monomers in the fibril are arranged in an antiparallel ␤-sheet conformation. Indeed, IR measurements, supported by tyrosine cross-linking experiments, provide a characteristic signature of the antiparallel ␤-sheet. We conclude that the self-assembly of A␤ is critically dependent on the hairpin turn and on the contact between the Phe 19 and Leu 34 regions, making them potentially sensitive targets for Alzheimer's therapeutics. Our results show the importance of specific conformations in an aggregation process thought to be primarily driven by nonspecific hydrophobic interactions.Alzheimer's disease pathology has been associated with the aggregation of amyloid ␤ (A␤), 6 a 39 -43-amino acid-long peptide (1, 2). In this process, the unstructured monomers of A␤ get converted into amyloid fibrils composed of hairpin-shaped monomeric units assembled in a parallel ␤ sheet arrangement (3, 4). The central part of this hairpin structure consists of a hydrophilic region flanked by hydrophobic ␤-sheet-forming segments at both ends (5-10). This particular shape is believed to be dictated by the specific pattern of hydrophobic and charged residues in the A␤ sequence and has been identified even in soluble A␤ aggregates (7,(11)(12)(13)(14)(15)(16)(17), including the very early stage oligomers of A␤ (18 , and stabilizes the soluble monomeric and oligomeric assemblies of A␤ (19). This hairpin turn thus seems to be a critical factor dictating the self-assembly of A␤ under physiological conditions. Studying the influence of the turn region on the properties of A␤, separately from that of the distal terminal regions and without changing the electrostatics, can yield valuable information on the logic of A␤ assembly.A␤ aggregation appears to be primarily hydrophobic in nature. In fact a contact between hydrophobic regions containing Phe 19 and Leu 34 is one of the earliest contacts formed during the aggregation of amyloid ␤ (18). In a generic hydrophobic aggregate, the burial of the hydrophobic surface can in principle proceed in an ...

show abstract

A folding transition underlies the emergence of membrane affinity in amyloid-β

Cited by 37 publications

References 38 publications

Maximally asymmetric transbilayer distribution of anionic lipids alters the structure and interaction with lipids of an amyloidogenic protein dimer bound to the membrane surface

Maximally asymmetric transbilayer distribution of anionic lipids alters the structure and interaction with lipids of an amyloidogenic protein dimer bound to the membrane surface

Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies

Steric Crowding of the Turn Region Alters the Tertiary Fold of Amyloid-β18–35 and Makes It Soluble

Contact Info

Product

Resources

About