University of Oulu

Raasakka A, Ruskamo S, Barker R, Krokengen OC, Vatne GH, Kristiansen CK, et al. (2019) Neuropathy-related mutations alter the membrane binding properties of the human myelin protein P0 cytoplasmic tail. PLoS ONE 14(6): e0216833.

Neuropathy-related mutations alter the membrane binding properties of the human myelin protein P0 cytoplasmic tail

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Author: Raasakka, Arne1; Ruskamo, Salla2,3; Barker, Robert4;
Organizations: 1Department of Biomedicine, University of Bergen, Bergen, Norway
2Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
3Biocenter Oulu, University of Oulu, Oulu, Finland
4School of Physical Sciences, University of Kent, Kent, United Kingdom
5SIS Neutron and Muon Source, Science & Technology Facilities Council, Rutherford Appleton Laboratory, Didcot, United Kingdom
6Division of Physical Chemistry, Department of Chemistry, Lund University, Lund, Sweden
7European Spallation Source ERIC, Lund, Sweden
8ISA, Department of Physics and Astronomy, Aarhus University, Aarhus C, Denmark
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.4 MB)
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Language: English
Published: Public Library of Science, 2019
Publish Date: 2020-03-12


Schwann cells myelinate selected axons in the peripheral nervous system (PNS) and contribute to fast saltatory conduction via the formation of compact myelin, in which water is excluded from between tightly adhered lipid bilayers. Peripheral neuropathies, such as Charcot-Marie-Tooth disease (CMT) and Dejerine-Sottas syndrome (DSS), are incurable demyelinating conditions that result in pain, decrease in muscle mass, and functional impairment. Many Schwann cell proteins, which are directly involved in the stability of compact myelin or its development, are subject to mutations linked to these neuropathies. The most abundant PNS myelin protein is protein zero (P0); point mutations in this transmembrane protein cause CMT subtype 1B and DSS. P0 tethers apposing lipid bilayers together through its extracellular immunoglobulin-like domain. Additionally, P0 contains a cytoplasmic tail (P0ct), which is membrane-associated and contributes to the physical properties of the lipid membrane. Six CMT- and DSS-associated missense mutations have been reported in P0ct. We generated recombinant disease mutant variants of P0ct and characterized them using biophysical methods. Compared to wild-type P0ct, some mutants have negligible differences in function and folding, while others highlight functionally important amino acids within P0ct. For example, the D224Y variant of P0ct induced tight membrane multilayer stacking. Our results show a putative molecular basis for the hypermyelinating phenotype observed in patients with this particular mutation and provide overall information on the effects of disease-linked mutations in a flexible, membrane-binding protein segment. Using neutron reflectometry, we additionally show that P0ct embeds deep into a lipid bilayer, explaining the observed effects of P0ct on the physical properties of the membrane.

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Series: PLoS one
ISSN: 1932-6203
ISSN-E: 1932-6203
ISSN-L: 1932-6203
Volume: 14
Issue: 6
Article number: e0216833
DOI: 10.1371/journal.pone.0216833
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was financially supported by the Academy of Finland (Finland) (PK), the Jane and Aatos Erkko Foundation (Finland) (PK), and the Norwegian Research Council (SYNKNØYT program) (PK). This work has been supported by iNEXT, grant number 653706 (PK), funded by the Horizon 2020 programme of the European Commission. The research leading to this result has been supported by the project CALIPSOplus under the Grant Agreement 730872 from the EU Framework Programme for Research and Innovation HORIZON 2020 (PK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
EU Grant Number: (653706) iNEXT - Infrastructure for NMR, EM and X-rays for translational research
Copyright information: © 2019 Raasakka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.