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

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 nerv...

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Autores principales:	Salla Ruskamo, Tuomo Nieminen, Cecilie K. Kristiansen, Guro H. Vatne, Anne Baumann, Erik I. Hallin, Arne Raasakka, Päivi Joensuu, Ulrich Bergmann, Ilpo Vattulainen, Petri Kursula
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/84b4f0e7f79a44c780fb0a432945a2ca
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spelling	oai:doaj.org-article:84b4f0e7f79a44c780fb0a432945a2ca2021-12-02T16:06:37ZMolecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P210.1038/s41598-017-06781-02045-2322https://doaj.org/article/84b4f0e7f79a44c780fb0a432945a2ca2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06781-0https://doaj.org/toc/2045-2322Abstract 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.Salla RuskamoTuomo NieminenCecilie K. KristiansenGuro H. VatneAnne BaumannErik I. HallinArne RaasakkaPäivi JoensuuUlrich BergmannIlpo VattulainenPetri KursulaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Salla Ruskamo Tuomo Nieminen Cecilie K. Kristiansen Guro H. Vatne Anne Baumann Erik I. Hallin Arne Raasakka Päivi Joensuu Ulrich Bergmann Ilpo Vattulainen Petri Kursula Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2
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.
format	article
author	Salla Ruskamo Tuomo Nieminen Cecilie K. Kristiansen Guro H. Vatne Anne Baumann Erik I. Hallin Arne Raasakka Päivi Joensuu Ulrich Bergmann Ilpo Vattulainen Petri Kursula
author_facet	Salla Ruskamo Tuomo Nieminen Cecilie K. Kristiansen Guro H. Vatne Anne Baumann Erik I. Hallin Arne Raasakka Päivi Joensuu Ulrich Bergmann Ilpo Vattulainen Petri Kursula
author_sort	Salla Ruskamo
title	Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2
title_short	Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2
title_full	Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2
title_fullStr	Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2
title_full_unstemmed	Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2
title_sort	molecular mechanisms of charcot-marie-tooth neuropathy linked to mutations in human myelin protein p2
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/84b4f0e7f79a44c780fb0a432945a2ca
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Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2

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