|Title||N-terminal Prion Protein Peptides (PrP120-144) Form Parallel In-register β-sheets via Multiple Nucleation-dependent Pathways|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Wang, Y, Shao, Q, Hall, CK|
|Journal||Journal of Biological Chemistry|
The prion diseases are a family of fatal neurodegenerative diseases associated with the misfolding and accumulation of normal prion protein (PrPC) into its pathogenic scrapie form (PrPSc). Understanding the fundamentals of prion protein aggregation and the molecular architecture of PrPSc is key to unravelling the pathology of prion diseases. Our work investigates the early-stage aggregation of three prion protein peptides, corresponding to residues 120 to 144 of human (Hu), bank vole (BV) and Syrian hamster (SHa) prion protein, from disordered monomers to β-sheet-rich fibrillar structures. Using discontinuous molecular dynamics simulation combined with the PRIME20 force field, we find that the Hu, BV and Sha PrP120-144 aggregate via multiple nucleation-dependent pathways to form U-shaped, S-shaped and Ω-shaped protofilaments. The S-shaped HuPrP120-144 protofilament is similar to the amyloid core structure of HuPrP112-141 predicted by Zweckstetter. HuPrP120-144 has a shorter aggregation lag phase than BVPrP120-144, followed by SHaPrP120-144, consistent with experimental findings. Two amino acid substitutions I138M and I139M retard the formation of parallel in-register β-sheet dimers during the nucleation stage by increasing sidechain-sidechain association and reducing sidechain interaction specificity. On average, HuPrP120-144 aggregates contain more parallel β-sheet content than those formed by BV and SHa PrP120-144. Deletion of C-terminal residues 138 to 144 prevents formation of fibrillar structures in agreement with experiment. This work sheds light on the amyloid core structures underlying prion strains and how I138M, I139M and S143N affect prion protein aggregation kinetics.