Stoichiometry and affinity of the human serum albumin-Alzheimer's A? peptide interactions.

ABSTRACT: A promising strategy to control the aggregation of the Alzheimer's A? peptide in the brain is the clearance of A? from the central nervous system into the peripheral blood plasma. Among plasma proteins, human serum albumin plays a critical role in the A? clearance to the peripheral sink by binding to A? oligomers and preventing further growth into fibrils. However, the stoichiometry and the affinities of the albumin-A? oligomer interactions are still to be fully characterized. For this purpose, here we investigate the A? oligomer-albumin complexes through a novel and generally applicable experimental strategy combining saturation transfer and off-resonance relaxation NMR experiments with ultrafiltration, domain deletions, and dynamic light scattering. Our results show that the A? oligomers are recognized by albumin through sites that are evenly partitioned across the three albumin domains and that bind the A? oligomers with similar dissociation constants in the 1-100 nM range, as assessed based on a Scatchard-like model of the albumin inhibition isotherms. Our data not only explain why albumin is able to inhibit amyloid formation at physiological nM A? concentrations, but are also consistent with the presence of a single high affinity albumin-binding site per A? protofibril, which avoids the formation of extended insoluble aggregates.

SUBMITTER: Milojevic J 

PROVIDER: S-EPMC3010178 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature