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The off-rate of monomers dissociating from amyloid-? protofibrils.

ABSTRACT: The interconversion of monomers, oligomers, and amyloid fibrils of the amyloid-? peptide (A?) has been implicated in the pathogenesis of Alzheimer disease. The determination of the kinetics of the individual association and dissociation reactions is hampered by the fact that forward and reverse reactions to/from different aggregation states occur simultaneously. Here, we report the kinetics of dissociation of A? monomers from protofibrils, prefibrillar high molecular weight oligomers previously shown to possess pronounced neurotoxicity. An engineered binding protein sequestering specifically monomeric A? was employed to follow protofibril dissociation by tryptophan fluorescence, precluding confounding effects of reverse or competing reactions. A? protofibril dissociation into monomers follows exponential decay kinetics with a time constant of ?2 h at 25 °C and an activation energy of 80 kJ/mol, values typical for high affinity biomolecular interactions. This study demonstrates the high kinetic stability of A? protofibrils toward dissociation into monomers and supports the delineation of the A? folding and assembly energy landscape.

SUBMITTER: Gruning CS

PROVIDER: S-EPMC3873566 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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The off-rate of monomers dissociating from amyloid-β protofibrils.

Grüning Clara S R CS Klinker Stefan S Wolff Martin M Schneider Mario M Toksöz Küpra K Klein Antonia N AN Nagel-Steger Luitgard L Willbold Dieter D Hoyer Wolfgang W

The Journal of biological chemistry 20131118 52

The interconversion of monomers, oligomers, and amyloid fibrils of the amyloid-β peptide (Aβ) has been implicated in the pathogenesis of Alzheimer disease. The determination of the kinetics of the individual association and dissociation reactions is hampered by the fact that forward and reverse reactions to/from different aggregation states occur simultaneously. Here, we report the kinetics of dissociation of Aβ monomers from protofibrils, prefibrillar high molecular weight oligomers previously ...[more]

PMID: 24247242

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Project description:Exchange dynamics between molecules free in solution and bound to the surface of a large supramolecular structure, a polymer, a membrane or solid support are important in many phenomena in biology and materials science. Here we present a novel and generally applicable solution NMR technique, known as dark-state exchange saturation transfer (DEST), to probe such exchange phenomena with atomic resolution. This is illustrated by the exchange reaction between amyloid-? (A?) monomers and polydisperse, NMR-invisible ('dark') protofibrils, a process of significant interest because the accumulation of toxic, aggregated forms of A?, from small oligomers to very large assemblies, has been implicated in the aetiology of Alzheimer's disease. The (15)N-DEST experiment imprints with single-residue-resolution dynamic information on the protofibril-bound species in the form of (15)N transverse relaxation rates ((15)N-R(2)) and exchange kinetics between monomers and protofibrils onto the easily observed two-dimensional (1)H-(15)N correlation spectrum of the monomer. The exchanging species on the protofibril surface comprise an ensemble of sparsely populated states where each residue is either tethered to (through other residues) or in direct contact with the surface. The first eight residues exist predominantly in a mobile tethered state, whereas the largely hydrophobic central region and part of the carboxy (C)-terminal hydrophobic region are in direct contact with the protofibril surface for a significant proportion of the time. The C-terminal residues of both A?40 and A?42 display lower affinity for the protofibril surface, indicating that they are likely to be surface exposed rather than buried as in structures of A? fibrils, and might therefore comprise the critical nucleus for fibril formation. The values, however, are significantly larger for the C-terminal residues of A?42 than A?40, which might explain the former's higher propensity for rapid aggregation and fibril formation.

Dataset Information

The off-rate of monomers dissociating from amyloid-? protofibrils.

Publications

The off-rate of monomers dissociating from amyloid-β protofibrils.

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