Selenomethionine incorporation into amyloid sequences regulates fibrillogenesis and toxicity

Abstract

Background: The capacity of a polypeptide chain to engage in an amyloid formation process and cause a conformational disease is contained in its sequence. Some of the sequences undergoing fibrillation contain critical methionine (Met) residues which in vivo can be synthetically substituted by selenomethionine (SeM) and alter their properties. Methodology/Principal Findings: Using peptide synthesis, biophysical techniques and cell viability determinations we have studied the effect of the substitution of methionine (Met) by selenomethionine (SeM) on the fibrillogenesis and toxic properties of Aβ40 and HuPrP(106-140). We have found that the effects display site-specificity and vary from inhibition of fibrillation and decreased toxicity ([SeM 35]Aβ40, [SeM 129]HuPrP(106-140) and [SeM 134]HuPrP(106-140)), retarded assembly, modulation of polymer shape and retention of toxicity ([SeM 112]HuPrP(106-140) to absence of effects ([SeM 109]HuPrP(106-140)). Conclusions/Significance: This work provides direct evidence that the substitution of Met by SeM in proamyloid sequences has a major impact on their self-assembly and toxic properties, suggesting that the SeM pool can play a major role in dictating the allowance and efficiency of a polypeptide chain to undergo toxic polymerization. © 2011 Martínez et al.