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

Autor: Raasakka A; Department of Biomedicine, University of Bergen, Bergen, Norway., Ruskamo S; Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.; Biocenter Oulu, University of Oulu, Oulu, Finland., Barker R; School of Physical Sciences, University of Kent, Kent, United Kingdom., Krokengen OC; Department of Biomedicine, University of Bergen, Bergen, Norway., Vatne GH; Department of Biomedicine, University of Bergen, Bergen, Norway., Kristiansen CK; Department of Biomedicine, University of Bergen, Bergen, Norway., Hallin EI; Department of Biomedicine, University of Bergen, Bergen, Norway., Skoda MWA; ISIS Neutron and Muon Source, Science & Technology Facilities Council, Rutherford Appleton Laboratory, Didcot, United Kingdom., Bergmann U; Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.; Biocenter Oulu, University of Oulu, Oulu, Finland., Wacklin-Knecht H; Division of Physical Chemistry, Department of Chemistry, Lund University, Lund, Sweden.; European Spallation Source ERIC, Lund, Sweden., Jones NC; ISA, Department of Physics and Astronomy, Aarhus University, Aarhus C, Denmark., Hoffmann SV; ISA, Department of Physics and Astronomy, Aarhus University, Aarhus C, Denmark., Kursula P; Department of Biomedicine, University of Bergen, Bergen, Norway.; Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2019 Jun 07; Vol. 14 (6), pp. e0216833. Date of Electronic Publication: 2019 Jun 07 (Print Publication: 2019).
DOI: 10.1371/journal.pone.0216833
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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