Molecular mechanisms of CharcotMarie-Tooth neuropathy linked to mutations in human myelin protein P2

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Ruskamo , S , Nieminen , T , Kristiansen , C K , Vatne , G H , Baumann , A , Hallin , E I , Raasakka , A , Joensuu , P , Bergmann , U , Vattulainen , I & Kursula , P 2017 , ' Molecular mechanisms of CharcotMarie-Tooth neuropathy linked to mutations in human myelin protein P2 ' , Scientific Reports , vol. 7 , 6510 . https://doi.org/10.1038/s41598-017-06781-0

Title: Molecular mechanisms of CharcotMarie-Tooth neuropathy linked to mutations in human myelin protein P2
Author: Ruskamo, Salla; Nieminen, Tuomo; Kristiansen, Cecilie K.; Vatne, Guro H.; Baumann, Anne; Hallin, Erik I.; Raasakka, Arne; Joensuu, Paivi; Bergmann, Ulrich; Vattulainen, Ilpo; Kursula, Petri
Contributor organization: Department of Physics
Date: 2017-07-26
Language: eng
Number of pages: 13
Belongs to series: Scientific Reports
ISSN: 2045-2322
DOI: https://doi.org/10.1038/s41598-017-06781-0
URI: http://hdl.handle.net/10138/215227
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 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.
Description: This article has an erratum: Doi 10.1038/s41598-017-18751-7
Subject: ACID-BINDING PROTEIN
FATTY-ACID
MEMBRANE-PROTEIN
INTERNAL WATER
SCHWANN-CELLS
DISEASE
LIGAND
DIFFRACTION
CRYSTALLIZATION
SIMULATIONS
217 Medical engineering
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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