Abstract
At the surface of Aβ(1-40) amyloid fibrils that have a threefold molecular symmetry (green in the left picture) a site of interaction of the glycosaminoglycan analogue heparin (blue) was identified. The binding site consists of residues at the N terminus and the turn regions defining the apices of the triangular geometry. Heparin has a lower affinity for Aβ(1-40) fibrils having twofold molecular symmetry, thus revealing a remarkable morphological selectivity.
Highlights
Over 30 proteins and peptides self-assemble into amyloid fibrils and plaques that are the pathological hallmark of human disorders; the most famous peptides are the 40- and 42-residue amyloid beta peptides Ab1-40 and Ab1-42 associated with Alzheimers disease (AD).[1]
How GAGs interact with Ab fibrils is not known, but the sequence H13HQK is a predicted heparin binding motif[9] and solid-state NMR (SSNMR) data suggest that the N-terminal arginine R5 is involved.[6]
Ab1-40 fibril morphology is highly dependent on assembly conditions,[11] and restraints from SSNMR experiments revealed that this polymorphism originates from differences in structure and organization at the molecular level.[12]
Summary
Over 30 proteins and peptides self-assemble into amyloid fibrils and plaques that are the pathological hallmark of human disorders; the most famous peptides are the 40- and 42-residue amyloid beta peptides Ab1-40 and Ab1-42 associated with Alzheimers disease (AD).[1]. Seeded 2A and 3Q fibrils that assembled in the presence of a fivefold mass excess of 5 kDa heparin appeared to be unaffected morphologically according to TEM (Figure 1 C). Spectra of the two fibril types in the presence of heparin collected using the differential absorbance technique, flow LD[13] (see the Supporting Information), were strikingly different from the spectra of the fibrils alone (Figure 1 B).
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