Abstract:
:Prions are the agents of a series of lethal neurodegenerative diseases. They are composed largely, if not entirely, of the host-encoded prion protein (PrP), which can exist in the cellular isoform PrP(C) and the pathological isoform PrP(Sc). The conformational change of the alpha-helical PrP(C) into beta-sheet-rich PrP(Sc) is the fundamental event of prion disease. The transition of recombinant PrP from a PrP(C)-like into a PrP(Sc)-like conformation can be induced in vitro by submicellar concentrations of SDS. An alpha-helical dimer was identified that might represent either the native state of PrP(C) or the first step from the monomeric PrP(C) to highly aggregated PrP(Sc). In the present study, the molecular structure of these dimers was analyzed by introducing covalent cross-links using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. Inter- and intramolecular bonds between directly neighboured amino groups and carboxy groups were generated. The bonds formed in PrP dimers of recombinant PrP (90-231) were identified by tryptic digestion and subsequent mass spectrometric analysis. Intra- and intermolecular cross-links between N-terminal glycine and three acidic amino acid side chains in the globular part of PrP were identified, showing the N-terminal amino acids (90-124) are not as flexible as known from NMR analysis. When the cross-linked sites were used as structural constraint, molecular modeling calculations yielded a structural model for PrP dimer and its monomeric subunit, including the folding of amino acids 90-124 in addition to the known structure. Molecular dynamics of the structure after release of the constraint indicated an intrinsic stability of the domain of amino acids 90-124.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Kaimann T,Metzger S,Kuhlmann K,Brandt B,Birkmann E,Höltje HD,Riesner Ddoi
10.1016/j.jmb.2007.11.035subject
Has Abstractpub_date
2008-02-15 00:00:00pages
582-96issue
2eissn
0022-2836issn
1089-8638pii
S0022-2836(07)01506-9journal_volume
376pub_type
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