Glycan-controlled epitopes of prion protein include a major determinant of susceptibility to sheep scrapie.
A key feature of prion encephalopathies is the accumulation of a misfolded form of the host glycoprotein PrP. Cell-free and cell culture studies have shown that the efficiency of conversion of PrP into the disease-associated form is influenced by its amino acid sequence and also by its carbohydrate moiety. Here, we characterize four novel glycoform-dependent monoclonal antibodies raised against prokaryotic recombinant sheep PrP. We demonstrate that these antibodies discriminate the PrP monoglycosylated species, since two of them recognize molecules that have the first Asn glycosylation site occupied (mono1) while the other two recognize molecules glycosylated at the second site (mono2). Remarkably, the recognition of PrP by the anti-mono2 antibodies was strongly influenced by the amino acid present at position 171, i.e., either Gln or Arg. This polymorphism is known to be the main determinant of susceptibility and resistance to scrapie in sheep. Altogether, our findings lead us to propose that each glycan chain controls the accessibility of PrP determinants located close upstream from their attachment site. The monoglycoform-assigned and the allotype-restricted antibodies described here, the first to date, should provide further opportunities to investigate the involvement of each glycan chain in PrP conversion in relation to prion strain diversity and the basis of the resistance conferred by the Arg-171 amino acid.
Moudjou
Mohammed
M
Virologie Immunologie Moléculaires, INRA, Jouy-en-Josas, France.
Treguer
Eric
E
Rezaei
Human
H
Sabuncu
Elifsu
E
Neuendorf
Erdmute
E
Groschup
Martin H
MH
Grosclaude
Jeanne
J
Laude
Hubert
H
Neuendorf
Erdi
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D001921:Brain / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology* / Q000502:physiology; D006031:Glycosylation; D051379:Mice; D011134:Polysaccharides / Q000276:immunology / Q000502:physiology*; D018621:PrPC Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D020033:Protein Isoforms / Q000737:chemistry / Q000276:immunology / Q000502:physiology; D012608:Scrapie / Q000209:etiology* / Q000276:immunology / Q000378:metabolism*; D012756:Sheep
D000911:Antibodies, Monoclonal; D000939:Epitopes; D011134:Polysaccharides; D018621:PrPC Proteins; D020033:Protein Isoforms