Human serum albumin inhibits Abeta fibrillization through a "monomer-competitor" mechanism.
Human serum albumin (HSA) is not only a fatty acid and drug carrier protein, it is also a potent inhibitor of Abeta self-association in plasma. However, the mechanism underlying the inhibition of Abeta fibrillization by HSA is still not fully understood. We therefore investigated the Abeta-HSA system using a combined experimental strategy based on saturation transfer difference (STD) NMR and intrinsic albumin fluorescence experiments on three Abeta peptides with different aggregation propensities (i.e., Abeta(12-28), Abeta(1-40), and Abeta(1-42)). Our data consistently show that albumin selectively binds to cross-beta-structured Abeta oligomers as opposed to Abeta monomers. The HSA/Abeta oligomer complexes have K(D) values in the micromolar to submicromolar range and compete with the further addition of Abeta monomers to the Abeta assemblies, thus inhibiting fibril growth ("monomer competitor" model). Other putative mechanisms, according to which albumin acts as a "monomer stabilizer" or a "dissociation catalyst", are not supported by our data, thus resolving previous discrepancies in the literature regarding Abeta-HSA interactions. In addition, the model and the experimental approaches proposed here are anticipated to have broad relevance for the characterization of other systems that involve amyloidogenic peptides and oligomerization inhibitors.
Milojevic
Julijana
J
Department of Chemistry and Chemical Biology, and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Raditsis
Annie
A
Melacini
Giuseppe
G
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001703:Biophysics / Q000379:methods*; D002384:Catalysis; D004337:Drug Carriers / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry*; D013050:Spectrometry, Fluorescence / Q000379:methods; D013997:Time Factors
D016229:Amyloid beta-Peptides; D004337:Drug Carriers; D010446:Peptide Fragments; D010455:Peptides; D012709:Serum Albumin; C075222:amyloid beta-protein (1-42)