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@ARTICLE{Pauly:909761,
      author       = {Pauly, Thomas and Bolakhrif, Najoua and Kaiser, Jesko and
                      Nagel-Steger, Luitgard and Gremer, Lothar and Gohlke, Holger
                      and Willbold, Dieter},
      title        = {{M}et/{V}al129 polymorphism of the full-length human prion
                      protein dictates distinct pathways of amyloid formation},
      journal      = {The journal of biological chemistry},
      volume       = {298},
      number       = {10},
      issn         = {0021-9258},
      address      = {Bethesda, MD.},
      publisher    = {American Soc. for Biochemistry and Molecular Biology},
      reportid     = {FZJ-2022-03391},
      pages        = {102430},
      year         = {2022},
      abstract     = {Methionine/valine polymorphism at position 129 of the human
                      prion protein, huPrP, is tightly associated with the
                      pathogenic phenotype, disease progress, and age of onset of
                      neurodegenerative diseases such as Creutzfeldt–Jakob
                      disease or Fatal Familial Insomnia. This raises the question
                      of whether and how the amino acid type at position 129
                      influences the structural properties of huPrP, affecting its
                      folding, stability, and amyloid formation behavior. Here,
                      our detailed biophysical characterization of the 129M and
                      129V variants of recombinant full-length huPrP(23–230) by
                      amyloid formation kinetics, CD spectroscopy, molecular
                      dynamics simulations, and sedimentation velocity analysis
                      reveals differences in their aggregation propensity and
                      oligomer content, leading to deviating pathways for the
                      conversion into amyloid at acidic pH. We determined that the
                      129M variant exhibits less secondary structure content
                      before amyloid formation and higher resistance to thermal
                      denaturation compared to the 129V variant, whereas the
                      amyloid conformation of both variants shows similar thermal
                      stability. Additionally, our molecular dynamics simulations
                      and rigidity analyses at the atomistic level identify
                      intramolecular interactions responsible for the enhanced
                      monomer stability of the 129M variant, involving more
                      frequent minimum distances between E196 and R156, forming a
                      salt bridge. Removal of the N-terminal half of the 129M
                      full-length variant diminishes its differences compared to
                      the 129V full-length variant and highlights the relevance of
                      the flexible N terminus in huPrP. Taken together, our
                      findings provide insight into structural properties of huPrP
                      and the effects of the amino acid identity at position 129
                      on amyloid formation behavior.},
      cin          = {IBG-4 / IBI-7 / JSC / NIC},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBG-4-20200403 / I:(DE-Juel1)IBI-7-20200312 /
                      I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)NIC-20090406},
      pnm          = {5111 - Domain-Specific Simulation $\&$ Data Life Cycle Labs
                      (SDLs) and Research Groups (POF4-511) / 2171 - Biological
                      and environmental resources for sustainable use (POF4-217) /
                      Forschergruppe Gohlke $(hkf7_20200501)$ / 5244 - Information
                      Processing in Neuronal Networks (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5111 / G:(DE-HGF)POF4-2171 /
                      $G:(DE-Juel1)hkf7_20200501$ / G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {36037966},
      UT           = {WOS:001088183800010},
      doi          = {10.1016/j.jbc.2022.102430},
      url          = {https://juser.fz-juelich.de/record/909761},
}