Methionine sulfoxides on PrPSc: a prion-specific covalent signature.
Prion diseases are fatal neurodegenerative disorders believed to be transmitted by PrP (Sc), an aberrant form of the membrane protein PrP (C). In the absence of an established form-specific covalent difference, the infectious properties of PrP (Sc) were uniquely ascribed to the self-perpetuation properties of its aberrant fold. Previous sequencing of the PrP chain isolated from PrP(27-30) showed the oxidation of some methionine residues; however, at that time, these findings were ascribed to experimental limitations. Using the unique recognition properties of alphaPrP mAb IPC2, protein chemistry, and state of the art mass spectrometry, we now show that while a large fraction of the methionine residues in brain PrP (Sc) are present as methionine sulfoxides this modification could not be found on brain PrP (C) as well as on its recombinant models. In particular, the pattern of oxidation of M213 with respect to the glycosylation at N181 of PrP (Sc) differs both within and between species, adding another diversity factor to the structure of PrP (Sc) molecules. Our results pave the way for the production of prion-specific reagents in the form of antibodies against oxidized PrP chains which can serve in the development of both diagnostic and therapeutic strategies. In addition, we hypothesize that the accumulation of PrP (Sc) and thereafter the pathogenesis of prion disease may result from the poor degradation of oxidized aberrantly folded PrP.
Canello
Tamar
T
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, 91120 Jerusalem, Israel.
Engelstein
Roni
R
Moshel
Ofra
O
Xanthopoulos
Konstantinos
K
Juanes
María E
ME
Langeveld
Jan
J
Sklaviadis
Theodoros
T
Gasset
Maria
M
Gabizon
Ruth
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002417:Cattle; D006224:Cricetinae; D004591:Electrophoresis, Polyacrylamide Gel; D019286:Endopeptidase K / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010084:Oxidation-Reduction / Q000187:drug effects; D018621:PrPC Proteins / Q000737:chemistry / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D012756:Sheep; D053719:Tandem Mass Spectrometry; D013853:Thioacetamide / Q000031:analogs & derivatives / Q000737:chemistry
D000911:Antibodies, Monoclonal; D000939:Epitopes; D018621:PrPC Proteins; D018620:PrPSc Proteins; D013853:Thioacetamide; C034455:N-methylmercaptoacetamide; D008715:Methionine; D006861:Hydrogen Peroxide; D019286:Endopeptidase K; C013111:methionine sulfoxide