Site-Specific Identification of an Aß Fibril-Heparin Interaction Site by Using Solid-State NMR Spectroscopy

We report the first detailed molecular insights into a recognition site for heparin, which is a proxy for GAG, within Aβ1-40 fibrils. GAGs are ubiquitous components of amyloid deposits in vivo and may be complicit in amyloid pathogenicity. A fascinating outcome of this work is the profound difference seen in the binding of heparin to the 2A and 3Q fibril types. The distinct packing geometries of the cross-b units of the 2A and 3Q fibrils may explain the different affinity of heparin for the two morphologies. Specifically, in the 3Q fibrils the N-terminal region lies in close proximity to the loop that links the two b strands in each monomer. This arrangement is not found in the 2A fibrils, thus possibly rationalizing the unique ability of heparin to bind tightly to fibrils of the 3Q type. Importantly, we show that GAG-amyloid interactions can differ according to the morphology of fibrils assembled from the same protein sequence. Further structural studies will be needed to determine how the binding site and mechanism differs in fibrils and their polymorphs formed from other protein sequences known to colocalize with GAGs, or how binding to the fibrils is influenced by GAG length. This work establishes a platform for such studies and for the structureinspired design of compounds that target GAG-polypeptide interactions for therapeutic or diagnostic purposes. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.