title: Interaction of the Heparin-Binding Consensus Sequence of β-Amyloid Peptides with Heparin and Heparin-Derived Oligosaccharides.
abstract: Alzheimer's disease (AD) is characterized by the presence of amyloid plaques in the AD brain. Comprised primarily of the 40- and 42-residue β-amyloid (Aβ) peptides, there is evidence that the heparan sulfate (HS) of heparan sulfate proteoglycans (HSPGs) plays a role in amyloid plaque formation and stability; however, details of the interaction of Aβ peptides with HS are not known. We have characterized the interaction of heparin and heparin-derived oligosaccharides with a model peptide for the heparin- and HS-binding domain of Aβ peptides (Ac-VHHQKLV-NH2; Aβ(12-18)), with mutants of Aβ(12-18), and with additional histidine-containing peptides. The nature of the binding interaction was characterized by NMR, binding constants and other thermodynamic parameters were determined by isothermal titration calorimetry (ITC), and relative binding affinities were determined by heparin affinity chromatography. The binding of Aβ(12-18) by heparin and heparin-derived oligosaccharides is pH-dependent, with the imidazolium groups of the histidine side chains interacting site-specifically within a cleft created by a trisaccharide sequence of heparin, the binding is mediated by electrostatic interactions, and there is a significant entropic contribution to the binding free energy as a result of displacement of Na(+) ions from heparin upon binding of cationic Aβ(12-18). The binding constant decreases as the size of the heparin-derived oligosaccharide decreases and as the concentration of Na(+) ion in the bulk solution increases. Structure-binding relationships characterized in this study are analyzed and discussed in terms of the counterion condensation theory of the binding of cationic peptides by anionic polyelectrolytes.
authors.affiliation: Department of Chemistry University of California, Riverside , Riverside, California 92521, United States.
authors.forename: Khanh
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry University of California, Riverside , Riverside, California 92521, United States.
authors.forename: Dallas L
authors.initials: DL
authors.lastname: Rabenstein
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001665:Binding Sites; D002151:Calorimetry; D006493:Heparin / Q000737:chemistry*; D009844:Oligosaccharides / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: C000612053:Ac-VHHQKLV-NH2; D016229:Amyloid beta-Peptides; D009844:Oligosaccharides; D010446:Peptide Fragments; D006493:Heparin