How do amino acid substitutions affect the amyloidogenic properties and seeding efficiency of prion peptides

Abstract

The amino acid sequences in the amyloidogenic region (amino acids 108–144) of several mammalian prion proteins were compared and variations were found to occur at residues 109 (M or L), 112 (M or V), 129 (M, V, or L), 135 (N or S), 138 (M, L, or I), 139 (M or I), and 143 (N or S). Using the bovine PrP peptide (residues 108–144 based on the numbering of the human prion protein sequence) as a control peptide, several peptides with one amino acid differing from that of the bovine PrP peptide at residues 109, 112, 135, 138, 139, or 143 and several mammalian PrP peptides were synthesized, and the effects of these amino acid substitutions on the amyloidogenic properties of these peptides were compared and discussed on the basis of the chemical and structural properties of amino acids. Our results showed that the V112M substitution accelerated nucleation of amyloidogenesis, while the N143S and I139M substitutions retarded nucleation. These effects tended to cancel each other out when two substitutions with opposite effects were present on the same peptide. Moreover, acceleration or inhibition of nucleation was not necessarily correlated with effect on seeding efficiency. Using amyloid fibrils prepared from the bovine PrP peptide as seeds, the seeding efficiency for the monomer peptides with the M129L, S135N, N143S, or I139M substitution was decreased compared to that for bPrP peptide. Of all the mammalian peptides used in this study, the dog, mule deer, and pig PrP peptides had the lowest seeding efficiencies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-013-1522-0) contains supplementary material, which is available to authorized users.

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

“…From the above analysis of simulation data, we conclude that S143N does not affect the aggregation kinetics of PrP(120 -144). Chuang et al (18), however, had a different finding on how Asn-Ser mutation affects PrP(108 -144) aggregation kinetics; they found that the single amino acid substitution N143S can retard bovine PrP(108 -144) aggregation.…”

“…In addition, Chuang et al (18) found in experiments that the I139M mutant of bovine PrP(108 -144) has a lag phase that is 4-fold longer than that of bovine PrP(108 -144).…”

“…Apostol et al (17) crystallized prion fragments corresponding to human (Hu)PrP(138 -143), MoPrP(137-142), and hamster PrP(138 -143) and found that HuPrP(138 -143) and MoPrP(137-142) form parallel in-register steric zippers, whereas hamster PrP(138 -143) forms antiparallel out-of-register steric zippers. Chuang et al (18) investigated how various amino acid substitutions in synthetic bovine PrP(108 -144) affect peptide amyloidogenesis and seeding efficiency. 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.…”

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

“…showed that residues 109, 112, and 139 determine the seeding and cross‐seeding efficiency of mouse and hamster PrP(108–144). Chuang et al . found that the mutation L138M promotes the amyloidogenesis of bovine PrP(108–144) peptide and increases its seeding efficiency while the mutations I139M and N143S do the opposite.…”

“…Experiments by Lee et al 15 showed that residues 109, 112, and 139 determine the seeding and cross-seeding efficiency of mouse and hamster PrP(108-144). Chuang et al 16 found that the mutation L138M promotes the amyloidogenesis of bovine PrP(108-144) peptide and increases its seeding efficiency while the mutations I139M and N143S do the opposite. Apostol et al 17 found that human and mouse PrP(138-143) fibrils both form parallel steric zippers while hamster PrP(138-143) fibril forms anti-parallel steric zippers.…”