Post-translational hydroxylation at the N-terminus of the prion protein reveals presence of PPII structure in vivo

Andy Gill, Mark A. Ritchie, Lawrence G. Hunt, Sarah E. Steane, Kenneth G. Davis, Sharon P. Bocking, Alexandre G. O. Rhie, Alan D. Bennett, James Hope

Research output: Contribution to journalArticlepeer-review

Abstract

The transmissible spongiform encephalopathies are characterized by conversion of a host protein, PrPC (cellular prion protein), to a protease-resistant isoform,
PrPSc (prion protein scrapie isoform). The importance of the highly-flexible, N-terminal region of PrP has recently become more widely appreciated, particularly the biological activities associated with its metal ion binding domain and its potential to form a poly(L-proline) II (PPII) helix. Circular dichroism spectroscopy of an N-terminal peptide, PrP37-53, showed that the PPII helix is formed in aqueous buffer; as it also contains a Xaa-Pro-Gly consensus sequence, it may act as a substrate for the collagen modifying enzyme prolyl 4-hydroxylase. Direct
evidence for this modifi-cation was obtained by mass spectrometry and Edman sequencing in recombinant mouse PrP secreted from stably transfected Chinese
hamster ovary cells. Almost complete conversion of proline to 4-hydroxyproline occurs specifically at residue Pro44 of this murine protein; the same hydroxylated
residue was detected, at lower levels, in PrPSc from the brains of scrapie infected mice. Cation binding and/or post-translational hydroxylation of this region of PrP may regulate its role in the physiology and pathobiology of the cell.
Original languageEnglish
Pages (from-to)5324-5331
JournalEMBO Journal
Volume19
Issue number20
Publication statusPublished - 2000

Keywords

  • 4-hydroxyproline
  • polyproline II helix
  • post-translational modification
  • prion protein
  • prolyl 4-hydroxylase

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