Elucidating\nthe Mechanism of Recognition and Binding\nof Heparin to Amyloid Fibrils of Serum Amyloid A

Amyloid diseases feature pathologic deposition of normally\nsoluble\nproteins and peptides as insoluble fibrils in vital organs. Amyloid\nfibrils co-deposit with various nonfibrillar components including\nheparan sulfate (HS), a glycosaminoglycan that promotes amyloid formation\nin vitro for many unrelated proteins. HS–amyloid interactions\nhave been proposed as a therapeutic target for inflammation-linked\namyloidosis wherein N-terminal fragments of serum amyloid A (SAA)\nprotein deposit in the kidney and liver. The structural basis for\nthese interactions is unclear. Here, we exploit the high-resolution\ncryoelectron microscopy (cryo-EM) structures of ex vivo murine and\nhuman SAA fibrils in a computational study employing molecular docking,\nBrownian dynamics simulations, and molecular dynamics simulations\nto elucidate how heparin, a highly sulfated HS mimetic, recognizes\nand binds to amyloid protein fibrils. Our results demonstrate that\nnegatively charged heparin chains bind to linear arrays of uncompensated\npositively charged basic residues along the spines of amyloid fibrils\nfacilitated by electrostatic steering. The predicted heparin binding\nsites match the location of unidentified densities observed in cryo-EM\nmaps of SAA amyloids, suggesting that these extra densities represent\nbound HS. Since HS is constitutively found in various amyloid deposits,\nour results suggest a common mechanism for HS–amyloid recognition\nand binding.