RT Journal Article
SR Electronic
T1 Neuropathy-related mutations alter the membrane binding properties of the human myelin protein P0 cytoplasmic tail
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 535013
DO 10.1101/535013
A1 Arne Raasakka
A1 Salla Ruskamo
A1 Robert Barker
A1 Oda C. Krokengen
A1 Guro H. Vatne
A1 Cecilie K. Kristiansen
A1 Erik I. Hallin
A1 Maximilian W.A. Skoda
A1 Ulrich Bergmann
A1 Hanna Wacklin-Knecht
A1 Nykola C. Jones
A1 Søren Vrønning Hoffmann
A1 Petri Kursula
YR 2019
UL http://biorxiv.org/content/early/2019/01/30/535013.1.abstract
AB 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.