Elucidating the Mechanism of Recognition and Binding of Heparin to Amyloid Fibrils of Serum Amyloid A.

Amyloid diseases feature pathologic deposition of normally soluble proteins and peptides as insoluble fibrils in vital organs. Amyloid fibrils co-deposit with various nonfibrillar components including heparan sulfate (HS), a glycosaminoglycan that promotes amyloid formation in vitro for many unrelated proteins. HS-amyloid interactions have been proposed as a therapeutic target for inflammation-linked amyloidosis wherein N-terminal fragments of serum amyloid A (SAA) protein deposit in the kidney and liver. The structural basis for these interactions is unclear. Here, we exploit the high-resolution cryoelectron microscopy (cryo-EM) structures of ex vivo murine and human SAA fibrils in a computational study employing molecular docking, Brownian dynamics simulations, and molecular dynamics simulations to elucidate how heparin, a highly sulfated HS mimetic, recognizes and binds to amyloid protein fibrils. Our results demonstrate that negatively charged heparin chains bind to linear arrays of uncompensated positively charged basic residues along the spines of amyloid fibrils facilitated by electrostatic steering. The predicted heparin binding sites match the location of unidentified densities observed in cryo-EM maps of SAA amyloids, suggesting that these extra densities represent bound HS. Since HS is constitutively found in various amyloid deposits, our results suggest a common mechanism for HS-amyloid recognition and binding.