Seeding and cross‐seeding fibrillation of N‐terminal prion protein peptides PrP(120–144)

Abstract

Prion diseases are infectious neurodegenerative diseases that are capable of cross-species transmission, thus arousing public health concerns. Seed-templating propagation of prion protein is believed to underlie prion cross-species transmission pathology. Understanding the molecular fundamentals of prion propagation is key to unravelling the pathology of prion diseases. In this study, we use coarse-grained molecular dynamics to investigate the seeding and cross-seeding aggregation of three prion protein fragments PrP(120-144) originating from human (Hu), bank vole (BV), and Syrian hamster (SHa). We find that the seed accelerates the aggregation of the monomer peptides by eliminating the lag phase. The monomer aggregation kinetics are mainly determined by the structure of the seed. The stronger the hydrophobic residues on the seed associate with each other, the higher the probability that the seed recruits monomer peptides to its surface/interface. For cross-seeding aggregation, we show that Hu has a strong tendency to adopt the conformation of the BV seed and vice versa; the Hu and BV monomers have a weak tendency to adopt the conformation of the SHa seed. These two findings are consistent with Apostol et al.'s experimental findings on PrP(138-143) and partially consistent with Jones et al.'s finding on PrP(23-144). We also identify several conformational mismatches when SHa cross-seeds BV and Hu peptides, indicating the existence of a cross-seeding barrier between SHa and the other two sequences. This study sheds light on the molecular mechanism of seed-templating aggregation of prion protein fragments underlying the sequence-dependent transmission barrier in prion diseases.

Structural basis for the complete resistance of the human prion protein mutant G127V to prion disease

“…Moreover, conformational conversion is triggered at the two β-strands, the α1 helix, the α2 helix, the β1-α1 loop, the α1-β2 loop, and the β2-α2 loop 34 , 35 , 62 – 67 . Notably, the more stable β-structure is formed by the segment of the N-terminus (residues 120–144), the earlier stages of misfolding are caused by 43 , 68 , 69 in MD, and a relatively short β-sheet core (residues 112–139) is capable of seeding the conversion to fibrils in vitro 70 . Nevertheless, the molecular mechanism underlying the disease-resistant effect of the G127V mutation still remains elusive.…”

Heterotypic interactions in amyloid function and disease

“…The former has been shown to promote unilateral nucleation of IAPP, albeit with a lower efficiency compared to homologous assembly, whereby these proteins harbour stretches sharing sequence homology [172]. Several additional proteins have been associated to templated amyloid cross-talk via sharing of common structural architectures [161,[173][174][175], with the list expanding even to cases of functional amyloids [176][177][178][179][180][181][182]. Finally, cross-seeding and heterotypic co-aggregation has also been demonstrated in cancer-associated aggregation pathologies, where mutant p53 causes sequence-dependent co-deposition of its homologs p63 and p73 by virtue of their similar APRs [183][184][185].…”

Recent Advances in Coarse-Grained Models for Biomolecules and Their Applications

“…Notably, this model has also been successful in describing the effect of crowding on amyloid beta (16)(17)(18)(19)(20)(21)(22) aggregation [111,112] and the inhibitory effect of polyphenols on Aβ fibril formation [54]. Recent applications of this model include the study of structural and kinetic details of co-aggregation of Aβ40 and Aβ16-22 peptides [113] and cross seeding in fibrillation of prion protein peptides [55,114]. These findings can be helpful in better understanding the molecular assembly of peptides and further for therapeutic purposes.…”

“…Effect of inhibitors on Aβ fibril formation [54]; co-aggregation of Aβ40 and Aβ16-22 peptides cross seeding in fibrillation of prion protein peptides [55] Bereau and Deserno Four beads per residue…”