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]

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

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vUnhvx
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