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@ARTICLE{Ruskamo:398517,
      author       = {Ruskamo, Salla and Nieminen, Tuomo and Kristiansen, Cecilie
                      K. and Vatne, Guro H. and Baumann, Anne and Hallin, Erik I.
                      and Raasakka, Arne and Joensuu, Päivi and Bergmann, Ulrich
                      and Vattulainen, Ilpo and Kursula, Petri},
      title        = {{M}olecular mechanisms of {C}harcot-{M}arie-{T}ooth
                      neuropathy linked to mutations in human myelin protein {P}2},
      journal      = {Scientific reports},
      volume       = {7},
      number       = {1},
      issn         = {2045-2322},
      address      = {London},
      publisher    = {Nature Publishing Group},
      reportid     = {PUBDB-2017-14087},
      pages        = {6510},
      year         = {2017},
      abstract     = {Charcot-Marie-Tooth (CMT) disease is one of the most common
                      inherited neuropathies. Recently, three CMT1-associated
                      point mutations (I43N, T51P, and I52T) were discovered in
                      the abundant peripheral myelin protein P2. These mutations
                      trigger abnormal myelin structure, leading to reduced nerve
                      conduction velocity, muscle weakness, and distal limb
                      atrophy. P2 is a myelin-specific protein expressed by
                      Schwann cells that binds to fatty acids and membranes,
                      contributing to peripheral myelin lipid homeostasis. We
                      studied the molecular basis of the P2 patient mutations.
                      None of the CMT1-associated mutations alter the overall
                      folding of P2 in the crystal state. P2 disease variants show
                      increased aggregation tendency and remarkably reduced
                      stability, T51P being most severe. In addition, P2 disease
                      mutations affect protein dynamics. Both fatty acid binding
                      by P2 and the kinetics of its membrane interactions are
                      affected by the mutations. Experiments and simulations
                      suggest opening of the β barrel in T51P, possibly
                      representing a general mechanism in fatty acid-binding
                      proteins. Our findings demonstrate that altered biophysical
                      properties and functional dynamics of P2 may cause myelin
                      defects in CMT1 patients. At the molecular level, a few
                      malformed hydrogen bonds lead to structural instability and
                      misregulation of conformational changes related to ligand
                      exchange and membrane binding.},
      cin          = {EMBL-User},
      ddc          = {000},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {6G3 - PETRA III (POF3-622)},
      pid          = {G:(DE-HGF)POF3-6G3},
      experiment   = {EXP:(DE-H253)P-P12-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28747762},
      UT           = {WOS:000406364600023},
      doi          = {10.1038/s41598-017-06781-0},
      url          = {https://bib-pubdb1.desy.de/record/398517},
}