Atomic-resolution map of the interactions between an amyloid inhibitor protein and amyloid {beta} (A{beta}) peptides in the monomer and protofibril states [Protein Structure and Folding] (Journal of Biological Chemistry)

Self-association of amyloid ? (A?) peptides is a hallmark of Alzheimer`s disease and serves as a general prototype for amyloid formation. A key endogenous inhibitor of A? self-association is human serum albumin (HSA), which binds ~90% of plasma A?. However, the exact molecular mechanism by which HSA binds A? monomers and protofibrils is not fully understood. Here, using dark-state exchange saturation transfer NMR and relaxation experiments complemented by morphological characterization, we mapped the HSA-A? interactions at atomic resolution by examining the effects of HSA on A? monomers and soluble high-molecular weight oligomeric protofibrils. We found that HSA binds both monomeric and protofibrillar A?, but the affinity of HSA for A? monomers is lower than for A? protofibrils (Kd values are submillimolar rather than micromolar) yet physiologically relevant because of the ~0.6-0.7 mm plasma HSA concentration. In both A? protofibrils and monomers, HSA targets key A? self-recognition sites spanning the ? strands found in cross-? protofibril structures, leading to a net switch from direct to tethered contacts between the monomeric A? and the protofibril surface. These HSA-A? interactions are isoform-specific, because the HSA affinity of A? monomers is lower for A?(1-42) than for A?(1-40). In addition, the HSA-induced perturbations of the monomer/protofibrils pseudo-equilibrium extend to the C-terminal residues in the A?(1-42) isoform but not in A?(1-40). These results provide an unprecedented view of how albumin interacts with A? and illustrate the potential of dark-state exchange saturation transfer NMR in mapping the interactions between amyloid-inhibitory proteins and amyloidogenic peptides.