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 ([SeM35]Aβ40, [SeM129]HuPrP(106–140) and [SeM134]HuPrP(106–140)), retarded assembly, modulation of polymer shape and retention of toxicity ([SeM112]HuPrP(106–140) to absence of effects ([SeM109]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.

This work was supported in part by gra’ts BFU2009-07975 (MG), BIO2008-04487-CO3-02 (DA) and BIO2008-00799 (EG) from the Spanish Ministry of Science and Innovation, from the Fundación Cien-Fundación Reina Sofia, and from Generalitat de Catalunya (XRB and Grups Consolidats). Wioleta Kowalczyk is supported by a Juan de la Cierva fellowship from the Spanish Ministry of Science and Innovation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip