N-terminal Prion Protein Peptides (PrP(120–144)) Form Parallel In-register β-Sheets via Multiple Nucleation-dependent Pathways

Yiming Wang,Qing Shao,Carol K Hall

doi:10.1074/jbc.m116.744573

Abstract

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 unraveling the pathology of prion diseases. Our work investigates the early-stage aggregation of three prion protein peptides, corresponding to residues 120-144 of human (Hu), bank vole (BV), and Syrian hamster (SHa) prion protein, from disordered monomers to β-sheet-rich fibrillar structures. Using 12 μs discontinuous molecular dynamics simulations combined with the PRIME20 force field, we find that the Hu-, BV-, and SHaPrP(120-144) aggregate via multiple nucleation-dependent pathways to form U-shaped, S-shaped, and Ω-shaped protofilaments. The S-shaped HuPrP(120-144) protofilament is similar to the amyloid core structure of HuPrP(112-141) predicted by Zweckstetter. HuPrP(120-144) has a shorter aggregation lag phase than BVPrP(120-144) followed by SHaPrP(120-144), 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 side chain-side chain association and reducing side chain interaction specificity. On average, HuPrP(120-144) aggregates contain more parallel β-sheet content than those formed by BV- and SHaPrP(120-144). Deletion of the C-terminal residues 138-144 prevents formation of fibrillar structures in agreement with the experiment. This work sheds light on the amyloid core structures underlying prion strains and how I138M, I139M, and S143N affect prion protein aggregation kinetics.

Highlights

Prion diseases are a family of infectious amyloid diseases that affect both humans and animals
Hu, bank vole (BV), and SHaPrP(120 –144) Aggregate into Protofilament Structures—We investigate the spontaneous fibrillation of prion protein fragments (PrP(120 –144)) by performing DMD/PRIME20 simulations on a system containing eight peptides
We find that the two amino acid substitutions I138M and I139M are responsible for retarding BV- and SHaPrP(120 –144) dimer formation compared with HuPrP(120 –144) and retard the aggregation kinetics

Summary

Introduction

Prion diseases are a family of infectious amyloid diseases that affect both humans and animals. DeMarco and Daggett [7] observed the conversion of native two-stranded ␤-sheets (residues 129 –131 and 161–163) in the Syrian hamster prion protein N terminus into three-stranded ␤-sheets (residues 116 –119, 129 –132, 160 –164) and isolated ␤-strands (residues 135–140) Based on this, they proposed a spiral ␤-helix filament model containing PrPSc-like trimers tightly packed along the fibril axis. Skora et al [15] applied H/D exchange coupled with NMR spectroscopy to fibrils formed by recombinant human PrP(108 –143) and found that residue 129 is deeply buried in the amyloid core. They found that mutations at position 129 greatly impact aggregation kinetics. They found that the mutation L138M promotes amyloid formation and increases seeding efficiency, whereas the mutations I139M and N143S retard amyloid formation and decrease PrP(108 –144) seeding efficiency

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