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Neuropathy-Related Mutations Alter the Membrane Binding Properties of the human 1 Myelin Protein P0 Cytoplasmic Tail

Raasakka, Arne, Ruskamo, Salla, Barker, Robert, Krokengen, Oda C., Vatne, Guro H., Kristiansen, Cecilie K., Hallin, Erik I., Skoda, M.W.A., Bergmann, Ulrich, Wacklin-Knecht, Hanna, and others. (2019) Neuropathy-Related Mutations Alter the Membrane Binding Properties of the human 1 Myelin Protein P0 Cytoplasmic Tail. PLOS ONE, . ISSN 1932-6203. (doi:10.1371/journal.pone.0216833)

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Abstract

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-4 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 8 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.

Item Type: Article
DOI/Identification number: 10.1371/journal.pone.0216833
Uncontrolled keywords: Myelin protein zero; membrane binding; peripheral neuropathy; CMT; DSS; disease mutation; gain of function
Divisions: Faculties > Sciences > School of Physical Sciences > Functional Materials Group
Depositing User: Robert Barker
Date Deposited: 08 May 2019 14:57 UTC
Last Modified: 23 Jan 2020 04:16 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/73803 (The current URI for this page, for reference purposes)
Barker, Robert: https://orcid.org/0000-0002-8645-5385
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