Lysine hydroxylation and O-glycosylation in the globular, C-terminal region of mammalian-expressed, recombinant PrP

Ritchie, Mark A., Hunt, Lawrence G. and Gill, Andrew C. (2012) Lysine hydroxylation and O-glycosylation in the globular, C-terminal region of mammalian-expressed, recombinant PrP. International Journal of Mass Spectrometry, 345-34 . pp. 132-141. ISSN 1387-3806

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Conversion of PrPC, the prion protein, to a conformationally altered isoform, PrPSc, is the major pathogenic event in the transmissible spongiform encephalopathies, a family of neurodegenerative diseases including bovine spongiform encephalopathy, Creutzfeldt-Jakob disease and scrapie. Known post-translational modifications to the protein include disulfide bridge formation, addition of a membrane anchor and N-linked glycosylation. We have previously identified the pro-collagen-like hydroxylation of proline 44 in a murine, recombinant prion protein expressed in Chinese hamster ovary cells and herein report the identification of a second pro-collagen-like modification in this protein. In a proportion of the molecules, Lys193, within the C-terminal, folded domain of the protein, is specifically modified to hydroxylysine with subsequent addition of two hexose units, assumed to be the collagen-like disaccharide modifier Gal-Glu. Proof of the existence of these modifications has been obtained by means of tandem mass spectrometry and Edman degradation. Molecular dynamics simulations show that these modifications lead to a pronounced stabilising effect on the β2–α2 loop, a region of PrP crucial for the disease-associated conversion. If present in vivo, these modifications may have important implications in PrP structure, interactions with ligands or may modulate PrP aggregation.

Keywords:prion protein, post translational modification, hydroxylysine, o-linked glycosylation, rigid loop
Subjects:C Biological Sciences > C770 Biophysical Science
C Biological Sciences > C760 Biomolecular Science
Divisions:College of Science
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ID Code:29468
Deposited On:10 Jan 2018 14:24

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