Mapping the interactions between the Alzheimer's A?-peptide and human serum albumin beyond domain resolution.

ABSTRACT: Human serum albumin (HSA) is a potent inhibitor of A? self-association and this novel, to our knowledge, function of HSA is of potential therapeutic interest for the treatment of Alzheimer's disease. It is known that HSA interacts with A? oligomers through binding sites evenly partitioned across the three albumin domains and with comparable affinities. However, as of this writing, no information is available on the HSA-A? interactions beyond domain resolution. Here, we map the HSA-A? interactions at subdomain and peptide resolution. We show that each separate subdomain of HSA domain 3 inhibits A? self-association. We also show that fatty acids (FAs) compete with A? oligomers for binding to domain 3, but the determinant of the HSA/A? oligomer interactions are markedly distinct from those of FAs. Although salt bridges with the FA carboxylate determine the FA binding affinities, hydrophobic contacts are pivotal for A? oligomer recognition. Specifically, we identified a site of A? oligomer recognition that spans the HSA (494-515) region and aligns with the central hydrophobic core of A?. The HSA (495-515) segment includes residues affected by FA binding and this segment is prone to self-associate into ?-amyloids, suggesting that sites involved in fibrilization may provide a lead to develop inhibitors of A? self-association.

SUBMITTER: Algamal M 

PROVIDER: S-EPMC3791307 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature