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@ARTICLE{Leliveld:62864,
      author       = {Leliveld, S. R. and Stitz, L. and Korth, C.},
      title        = {{E}xpansion of the octarepeat domain alters the misfolding
                      pathway but not the folding pathway of the prion protein},
      journal      = {Biochemistry},
      volume       = {47},
      issn         = {0006-2960},
      address      = {Columbus, Ohio},
      publisher    = {American Chemical Society},
      reportid     = {PreJuSER-62864},
      pages        = {6267 - 6278},
      year         = {2008},
      note         = {Record converted from VDB: 12.11.2012},
      abstract     = {A misfolded conformation of the prion protein (PrP), PrP
                      (Sc), is the essential component of prions, the infectious
                      agents that cause transmissible neurodegenerative diseases.
                      Insertional mutations that lead to an increase in the number
                      of octarepeats (ORs) in PrP are linked to familial human
                      prion disease. In this study, we investigated how expansion
                      of the OR domain causes PrP to favor a prion-like
                      conformation. Therefore, we compared the conformational and
                      aggregation modulating properties of wild-type versus
                      expanded OR domains, either as a fusion construct with the
                      protein G B1 domain (GB1-OR) or as an integral part of
                      full-length mouse PrP (MoPrP). Using circular dichroism
                      spectroscopy, we first demonstrated that ORs are not
                      unfolded but exist as an ensemble of three distinct
                      conformers: polyproline helix-like, beta-turn, and
                      "Trp-related". Domain expansion had little effect on the
                      conformation of GB1-OR fusion proteins. When part of MoPrP
                      however, OR domain expansion changed PrP's folding
                      landscape, not by hampering the production of native
                      alpha-helical monomers but by greatly reducing the
                      propensity to form amyloid and by altering the assembly of
                      misfolded, beta-rich aggregates. These features may relate
                      to subtle pH-dependent conformational differences between
                      wild-type and mutant monomers. In conclusion, we propose
                      that PrP insertional mutations are pathogenic because they
                      enhance specific misfolding pathways of PrP rather than by
                      undermining native folding. This idea was supported by a
                      trial bioassay in transgenic mice overexpressing wild-type
                      MoPrP, where intracerebral injection of recombinant MoPrP
                      with an expanded OR domain but not wild-type MoPrP caused
                      prion disease.},
      keywords     = {Animals / Circular Dichroism / Kinetics / Mice /
                      Mutagenesis, Insertional / Open Reading Frames / PrPSc
                      Proteins: chemistry / PrPSc Proteins: genetics / PrPSc
                      Proteins: metabolism / Prions: chemistry / Prions: genetics
                      / Prions: metabolism / Protein Conformation / Protein
                      Denaturation / Protein Folding / Recombinant Proteins:
                      chemistry / Repetitive Sequences, Amino Acid / Thrombin /
                      PrPSc Proteins (NLM Chemicals) / Prions (NLM Chemicals) /
                      Recombinant Proteins (NLM Chemicals) / Thrombin (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:18473442},
      UT           = {WOS:000256405800020},
      doi          = {10.1021/bi800253c},
      url          = {https://juser.fz-juelich.de/record/62864},
}