University of Oulu

Ruskamo, S., Nieminen, T., Kristiansen, C., Vatne, G., Baumann, A., Hallin, E., Raasakka, A., Joensuu, P., Bergmann, U., Vattulainen, I., Kursula, P. (2017) Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2. Scientific Reports, 7 (1), doi:10.1038/s41598-017-06781-0

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

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Author: Ruskamo, Salla1; Nieminen, Tuomo2; Kristiansen, Cecilie K.3;
Organizations: 1Faculty of Biochemistry and Molecular Medicine, University of Oulu
2Department of Physics, Tampere University of Technology
3Department of Biomedicine, University of Bergen
4Division of Psychiatry, Haukeland University Hospital
5Department of Sustainable Chemistry, Technical Faculty, University of Oulu
6Biocenter Oulu, University of Oulu
7Department of Physics, University of Helsinki
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5.1 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe201709198651
Language: English
Published: Nature Publishing Group, 2017
Publish Date: 2017-09-19
Description:

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.

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Volume: 7
Article number: 6510
DOI: 10.1038/s41598-017-06781-0
OADOI: https://oadoi.org/10.1038/s41598-017-06781-0
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
3111 Biomedicine
3124 Neurology and psychiatry
Subjects:
Funding: This study was funded by the Academy of Finland grant 275225 (SR), the Academy of Finland Center of Excellence program (IV, TN), European Research Council (CROWDED-PRO-LIPIDS) (IV), Western Norway Regional Health Authority (AB), Sigrid Jusélius Foundation (PK), Emil Aaltonen Foundation (PK), and the Norwegian Research Council SYNKNØYT programme (PK). The use of the facilities and expertise of the Biocenter Oulu protein crystallography core facility, a member of Biocenter Finland and Instruct-FI, is gratefully acknowledged. We also thank Ilkka Miinalainen, Jarkko Koivunen, and Hongmin Tu for assistance and the Biocenter Oulu core facilities for Proteomics and protein analysis and Electron microscopy. We extend our special thanks to synchrotron beamline support at SOLEIL, ANKA, EMBL/DESY, and DIAMOND.
Academy of Finland Grant Number: 275225
Detailed Information: 275225 (Academy of Finland Funding decision)
Dataset Reference: The crystal structure coordinates and structure factors are available at the PDB with the entry codes 5N4M (I43N), 5N4P (I52T), and 5N4Q (T51P). Other datasets analysed during the current study are available from the corresponding author upon reasonable request.
Copyright information: © The Author(s) 2017. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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