Aarhus University Seal / Aarhus Universitets segl

Søren Vrønning Hoffmann

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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

  • Arne Raasakka, University of Bergen, Norge
  • Salla Ruskamo, University of Oulu, Finland
  • Robert Barker, University of Kent, Storbritannien
  • Oda C. Krokengen, University of Bergen, Norge
  • Guro H. Vatne, University of Bergen, Norge
  • Cecilie K. Kristensen, University of Bergen, Norge
  • Erik I. Hallin, University of Bergen, Norge
  • Maximillian W. A. Skoda, ISIS, Rutherford Appleton Laboratory, Oxfordshire, Storbritannien
  • Ulrich Bergmann, University of Oulu, Finland
  • Hanna Wacklin-Knecht, Lund University, European Spallation Source ERIC, 22100 Lund, Sverige
  • Nykola C. Jones
  • Søren Vrønning Hoffmann
  • Petri Kursula, University of Bergen, University of Oulu, Norge

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.

OriginalsprogEngelsk
Artikelnummere0216833
TidsskriftPLOS ONE
Vol/bind14
Nummer6
Antal sider24
ISSN1932-6203
DOI
StatusUdgivet - 2019

Se relationer på Aarhus Universitet Citationsformater

ID: 157360746