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NMR structure of the water soluble A?17-34 peptide.

ABSTRACT: Alzheimer's disease is the most common neurodegenerative disorder in the world. Its most significant symptoms are memory loss and decrease in cognition. Alzheimer's disease is characterized by aggregation of two proteins in the brain namely A? (amyloid ?) and tau. Recent evidence suggests that the interaction of soluble A? with nAChR (nicotinic acetylcholine receptors) contributes to disease progression. In this study, we determine the NMR structure of an A?17-34 peptide solubilized by the addition of two glutamic acids at each terminus. Our results indicate that the A? peptide adopts an ?-helical structure for residues 19-26 and 28-33. The ?-helical structure is broken around residues S26, N27 and K28, which form a kink in the helical conformation. This ?-helix was not described earlier in an aqueous solution without organic solvents, and at physiological conditions (pH 7). These data are in agreement with A? adopting an ?-helical conformation in the membrane before polymerizing into amyloid ?-sheets and provide insight into the intermediate state of A? in Alzheimer's disease.

SUBMITTER: Fonar G

PROVIDER: S-EPMC4242080 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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NMR structure of the water soluble Aβ17-34 peptide.

Fonar Genadiy G Samson Abraham O AO

Bioscience reports 20141124 6

Alzheimer's disease is the most common neurodegenerative disorder in the world. Its most significant symptoms are memory loss and decrease in cognition. Alzheimer's disease is characterized by aggregation of two proteins in the brain namely Aβ (amyloid β) and tau. Recent evidence suggests that the interaction of soluble Aβ with nAChR (nicotinic acetylcholine receptors) contributes to disease progression. In this study, we determine the NMR structure of an Aβ17-34 peptide solubilized by the addit ...[more]

PMID: 25284368

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Project description:Hyperpolarized (129)Xe chemical exchange saturation transfer ((129)Xe Hyper-CEST) NMR is a powerful technique for the ultrasensitive, indirect detection of Xe host molecules (e.g., cryptophane-A). Irradiation at the appropriate Xe-cryptophane resonant radio frequency results in relaxation of the bound hyperpolarized (129)Xe and rapid accumulation of depolarized (129)Xe in bulk solution. The cryptophane effectively "catalyzes" this process by providing a unique molecular environment for spin depolarization to occur, while allowing xenon exchange with the bulk solution during the hyperpolarized lifetime (T(1) ≈ 1 min). Following this scheme, a triacetic acid cryptophane-A derivative (TAAC) was indirectly detected at 1.4 picomolar concentration at 320 K in aqueous solution, which is the record for a single-unit xenon host. To investigate this sensitivity enhancement, the xenon binding kinetics of TAAC in water was studied by NMR exchange lifetime measurement. At 297 K, k(on) ≈ 1.5 × 10(6) M(-1) s(-1) and k(off) = 45 s(-1), which represent the fastest Xe association and dissociation rates measured for a high-affinity, water-soluble xenon host molecule near rt. NMR line width measurements provided similar exchange rates at rt, which we assign to solvent-Xe exchange in TAAC. At 320 K, k(off) was estimated to be 1.1 × 10(3) s(-1). In Hyper-CEST NMR experiments, the rate of (129)Xe depolarization achieved by 14 pM TAAC in the presence of radio frequency (RF) pulses was calculated to be 0.17 μM·s(-1). On a per cryptophane basis, this equates to 1.2 × 10(4)(129)Xe atoms s(-1) (or 4.6 × 10(4) Xe atoms s(-1), all Xe isotopes), which is more than an order of magnitude faster than k(off), the directly measurable Xe-TAAC exchange rate. This compels us to consider multiple Xe exchange processes for cryptophane-mediated bulk (129)Xe depolarization, which provide at least 10(7)-fold sensitivity enhancements over directly detected hyperpolarized (129)Xe NMR signals.

Dataset Information

NMR structure of the water soluble A?17-34 peptide.

Publications

NMR structure of the water soluble Aβ17-34 peptide.

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