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Title: Assessing the Role of Oxidized Methionine at Position 213 in the Formation of Prions in Hamsters

Author
item Silva, Christopher - Chris
item ONISKO, BRUCE - Former ARS Employee
item Dynin, Irina
item Erickson-Beltran, Melissa
item Vensel, William
item REQUENA, JESUS - University Of Santiago De Compostela
item Antaki, Elizabeth
item Carter, John

Submitted to: Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/2/2010
Publication Date: 3/9/2010
Citation: Silva, C.J., Onisko, B.C., Dynin, I.A., Erickson, M.L., Vensel, W.H., Requena, J., Antaki, E.M., Carter, J.M. 2010. Assessing the Role of Oxidized Methionine at Position 213 in the Formation of Prions in Hamsters. Journal of Biochemistry. (49):1854-1861.

Interpretive Summary: Prions are infectious proteins that are able to recruit a normal cellular prion protein and convert it into a prion. Work by other researchers has suggested that the oxidized form of the amino acid methionine at position 213 of the prion protein (Met213) plays a role in the conversion of the normal cellular prion protein to the prion. We developed a sensitive method of determining the amount of the oxidized form of the amino acid methionine present at position 213 (MetSO213) of the prion protein. We used this method to determine the amount of MetSO213 present in the prion protein during the course of a prion infection. We examined the quantity of MetSO213 in normal cellular prion protein and compared it to the amount found in animals terminally afflicted with three strains of hamster-adapted prions. These results indicate that the amount of MetSO213 present in the prion protein remains less than 10 percent of the total over the disease course. The amount of MetSO213 present in three strains examined was similarly low. The amount of MetSO213 present in the normal cellular prion protein was also low. We conclude that MetSO213 has no apparent role in the formation of prions nor does it appear to be a prion-specific covalent signature.

Technical Abstract: Prions are infectious proteins that are able to recruit a normal cellular prion protein and convert it into a prion. The mechanism of this conversion is unknown. Detailed mass spectrometric analysis of the normal cellular prion protein and a corresponding prion has shown they possess identical post-translational modifications and differ solely in conformation. More recent work has suggested that the oxidized form of the methionine at position 213 (Met213) plays a role in the conversion of the normal cellular prion protein to the prion conformation. We developed a sensitive method of quantitating the amount of methionine sulfoxide present at position 213 (MetSO213). We used this method to quantitate the amount of MetSO213 over the time course of an ic challenge using the 263K strain of hamster adapted scrapie. We examined the quantity of MetSO213 in PrPC and compared it to the amount found in animals terminally afflicted with the 263K, 139H and drowsy strains of hamster-adapted prions. These results indicate that the proportion of Met213 that is oxidized remains less than 10% of the total over the disease course. Furthermore, all of the strains examined show only low levels (< 10%) of MetSO213 that is comparable to that of PrPC. MetSO213 has no apparent role in the formation of prions nor does it appear to be a prion-specific covalent signature.