Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2
| Autor: | Salla Ruskamo, Erik I. Hallin, Guro Helén Vatne, Arne Raasakka, Päivi Joensuu, Ulrich Bergmann, Ilpo Vattulainen, Petri Kursula, Anne Baumann, Cecilie Katrin Kristiansen, Tuomo Nieminen |
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| Přispěvatelé: | Department of Physics, Tampere University, Physics, Research area: Computational Physics, Research group: Biological Physics and Soft Matter |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
SCHWANN-CELLS Proteolipid protein 1 Science INTERNAL WATER ACID-BINDING PROTEIN Biology DIFFRACTION 114 Physical sciences Article DISEASE 03 medical and health sciences Myelin 0302 clinical medicine Atrophy Fatty acid binding molecular biophysics medicine demyelinating diseases structural biology Multidisciplinary FATTY-ACID MEMBRANE-PROTEIN Point mutation 217 Medical engineering Ligand (biochemistry) medicine.disease SIMULATIONS 3. Good health Cell biology 030104 developmental biology medicine.anatomical_structure Structural biology Biochemistry Membrane protein 3121 General medicine internal medicine and other clinical medicine ddc:000 Medicine LIGAND CRYSTALLIZATION 030217 neurology & neurosurgery |
| Zdroj: | Scientific reports 7(1), 6510 (2017). doi:10.1038/s41598-017-06781-0 Scientific Reports Scientific Reports, Vol 7, Iss 1, Pp 1-13 (2017) |
| Popis: | This article has an erratum: Doi 10.1038/s41598-017-18751-7 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 beta 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. |
| Databáze: | OpenAIRE |
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