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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2017-07-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-06781-0 |
| _version_ | 1818682622424907776 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-17T10:21:46Z |
| format | Article |
| id | doaj.art-84b4f0e7f79a44c780fb0a432945a2ca |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-17T10:21:46Z |
| publishDate | 2017-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-84b4f0e7f79a44c780fb0a432945a2ca2022-12-21T21:52:46ZengNature PortfolioScientific Reports2045-23222017-07-017111310.1038/s41598-017-06781-0Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2Salla Ruskamo0Tuomo Nieminen1Cecilie K. Kristiansen2Guro H. Vatne3Anne Baumann4Erik I. Hallin5Arne Raasakka6Päivi Joensuu7Ulrich Bergmann8Ilpo Vattulainen9Petri Kursula10Faculty of Biochemistry and Molecular Medicine, University of OuluDepartment of Physics, Tampere University of TechnologyDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenDepartment of Sustainable Chemistry, Technical Faculty, University of OuluFaculty of Biochemistry and Molecular Medicine, University of OuluDepartment of Physics, Tampere University of TechnologyFaculty of Biochemistry and Molecular Medicine, University of OuluAbstract 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.https://doi.org/10.1038/s41598-017-06781-0 |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-017-06781-0 |
| work_keys_str_mv | AT sallaruskamo molecularmechanismsofcharcotmarietoothneuropathylinkedtomutationsinhumanmyelinproteinp2 AT tuomonieminen molecularmechanismsofcharcotmarietoothneuropathylinkedtomutationsinhumanmyelinproteinp2 AT ceciliekkristiansen molecularmechanismsofcharcotmarietoothneuropathylinkedtomutationsinhumanmyelinproteinp2 AT gurohvatne molecularmechanismsofcharcotmarietoothneuropathylinkedtomutationsinhumanmyelinproteinp2 AT annebaumann molecularmechanismsofcharcotmarietoothneuropathylinkedtomutationsinhumanmyelinproteinp2 AT erikihallin molecularmechanismsofcharcotmarietoothneuropathylinkedtomutationsinhumanmyelinproteinp2 AT arneraasakka molecularmechanismsofcharcotmarietoothneuropathylinkedtomutationsinhumanmyelinproteinp2 AT paivijoensuu molecularmechanismsofcharcotmarietoothneuropathylinkedtomutationsinhumanmyelinproteinp2 AT ulrichbergmann molecularmechanismsofcharcotmarietoothneuropathylinkedtomutationsinhumanmyelinproteinp2 AT ilpovattulainen molecularmechanismsofcharcotmarietoothneuropathylinkedtomutationsinhumanmyelinproteinp2 AT petrikursula molecularmechanismsofcharcotmarietoothneuropathylinkedtomutationsinhumanmyelinproteinp2 |