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@ARTICLE{Kaimann:314,
author = {Kaimann, T. and Metzger, S. and Kuhlmann, K. and Brandt, B.
and Birkmann, E. and Höltje, H.-D. and Riesner, D.},
title = {{M}olecular {M}odel of an alpha-helical {P}rion {P}rotein
dimer and its monomeric subunits as derived from chemical
cross-linking and molecular modeling calculations},
journal = {Journal of molecular biology},
volume = {376},
issn = {0022-2836},
address = {Amsterdam [u.a.]},
publisher = {Elsevier},
reportid = {PreJuSER-314},
pages = {582 - 596},
year = {2008},
note = {Record converted from VDB: 12.11.2012},
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.},
keywords = {Amino Acids, Acidic: chemistry / Animals / Circular
Dichroism / Computer Simulation / Cricetinae / Cross-Linking
Reagents: chemistry / Dimerization / Mesocricetus / Models,
Molecular / Nuclear Magnetic Resonance, Biomolecular /
Prions: chemistry / Prions: genetics / Prions: metabolism /
Protein Conformation / Protein Isoforms: chemistry / Protein
Isoforms: metabolism / Protein Structure, Secondary /
Recombinant Proteins: chemistry / Recombinant Proteins:
metabolism / Spectrometry, Mass, Electrospray Ionization /
Tandem Mass Spectrometry / Trypsin: pharmacology / Amino
Acids, Acidic (NLM Chemicals) / Cross-Linking Reagents (NLM
Chemicals) / Prions (NLM Chemicals) / Protein Isoforms (NLM
Chemicals) / Recombinant Proteins (NLM Chemicals) / Trypsin
(NLM Chemicals) / J (WoSType)},
cin = {INB-2},
ddc = {570},
cid = {I:(DE-Juel1)VDB805},
pnm = {Funktion und Dysfunktion des Nervensystems},
pid = {G:(DE-Juel1)FUEK409},
shelfmark = {Biochemistry $\&$ Molecular Biology},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:18158160},
UT = {WOS:000253554700024},
doi = {10.1016/j.jmb.2007.11.035},
url = {https://juser.fz-juelich.de/record/314},
}