Curcumin Alters the Salt Bridge-containing Turn Region in Amyloid β(1–42) Aggregates

Mithu, Venus Singh; Sarkar, Bidyut; Bhowmik, Debanjan; Das, Anand Kant; Chandrakesan, Muralidharan; Maiti, Sudipta; Madhu, Perunthiruthy K.

doi:10.1074/jbc.m113.519447

Cited by 57 publications

(59 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S ⌬G25 was found to reach a C sat of 566 Ϯ 150 M in 7 days. S on the other hand attains a C sat of ϳ18 Ϯ 2 M over a similar period, which is close to the full-length A␤ 40 (ϳ12 Ϯ 4 M). Thus, deletion of a single residue Gly 25 caused the solubility of A␤ 18 -35 fragment to increase by more than 20 times under physiological buffer conditions.…”

Section: Resultsmentioning

confidence: 70%

“…Infrared Studies-200 M of A␤ 40 , 200 M A␤ ⌬G25 , and 1 mM of S ⌬G25 were incubated separately for 72 h in phosphate buffer (pH 7.4). All the solutions were subsequently centrifuged at 16,000 ϫ g for 15 min, and the supernatants were discarded.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, many of the properties were also compared with those of ⌬G29 and G25P mutants of S (hereafter called S ⌬G29 and S G25P , respectively) and the ⌬G25 mutant of full-length A␤ 40 (hereafter called A␤ ⌬G25 ). S ⌬G29 examines whether the position of the glycine deletion is critical.…”

mentioning

confidence: 99%

“…The secondary conformation of the peptides in the solution state is probed using thioflavin-T (thio-T) binding, CD, and solution state NMR. The effect of S and S ⌬G25 on the aggregation and fibril formation traits of A␤ 40 were probed by performing cross-seeding experiments with peptide mixtures. The morphology of the aggregates formed by S ⌬G25 and A␤ ⌬G25 were probed by transmission electron microscopy.…”

mentioning

confidence: 99%

“…V-530; Jasco) was used for all measurements with necessary day to day blank corrections. To assess the effect of possible cross-seeding, aggregation kinetics of 100 M A␤ 40 in presence of 100 M S or S ⌬G25 were monitored using the fluorescence of tyrosine remaining in the supernatant with time.…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

Section: Resultsmentioning

confidence: 70%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations