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

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Neuropathy-related mutations alter the membrane binding properties of the human myelin protein P0 cytoplasmic tail. / Raasakka, Arne; Ruskamo, Salla; Barker, Robert; Krokengen, Oda C.; Vatne, Guro H.; Kristiansen, Cecilie K.; Hallin, Erik I.; Skoda, Maximilian W.A.; Bergmann, Ulrich; Wacklin-Knecht, Hanna; Jones, Nykola C.; Hoffmann, Søren V.; Kursula, Petri.

In: PLoS ONE, Vol. 14, No. 6, e0216833, 2019.

Research output: Contribution to journalArticle

Harvard

Raasakka, A, Ruskamo, S, Barker, R, Krokengen, OC, Vatne, GH, Kristiansen, CK, Hallin, EI, Skoda, MWA, Bergmann, U, Wacklin-Knecht, H, Jones, NC, Hoffmann, SV & Kursula, P 2019, 'Neuropathy-related mutations alter the membrane binding properties of the human myelin protein P0 cytoplasmic tail', PLoS ONE, vol. 14, no. 6, e0216833. https://doi.org/10.1371/journal.pone.0216833

APA

Raasakka, A., Ruskamo, S., Barker, R., Krokengen, O. C., Vatne, G. H., Kristiansen, C. K., Hallin, E. I., Skoda, M. W. A., Bergmann, U., Wacklin-Knecht, H., Jones, N. C., Hoffmann, S. V., & Kursula, P. (2019). Neuropathy-related mutations alter the membrane binding properties of the human myelin protein P0 cytoplasmic tail. PLoS ONE, 14(6), [e0216833]. https://doi.org/10.1371/journal.pone.0216833

CBE

Raasakka A, Ruskamo S, Barker R, Krokengen OC, Vatne GH, Kristiansen CK, Hallin EI, Skoda MWA, Bergmann U, Wacklin-Knecht H, Jones NC, Hoffmann SV, Kursula P. 2019. Neuropathy-related mutations alter the membrane binding properties of the human myelin protein P0 cytoplasmic tail. PLoS ONE. 14(6):Article e0216833. https://doi.org/10.1371/journal.pone.0216833

MLA

Vancouver

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Raasakka, Arne ; Ruskamo, Salla ; Barker, Robert ; Krokengen, Oda C. ; Vatne, Guro H. ; Kristiansen, Cecilie K. ; Hallin, Erik I. ; Skoda, Maximilian W.A. ; Bergmann, Ulrich ; Wacklin-Knecht, Hanna ; Jones, Nykola C. ; Hoffmann, Søren V. ; Kursula, Petri. / Neuropathy-related mutations alter the membrane binding properties of the human myelin protein P0 cytoplasmic tail. In: PLoS ONE. 2019 ; Vol. 14, No. 6.

RIS

TY - JOUR

T1 - Neuropathy-related mutations alter the membrane binding properties of the human myelin protein P0 cytoplasmic tail

AU - Raasakka, Arne

AU - Ruskamo, Salla

AU - Barker, Robert

AU - Krokengen, Oda C.

AU - Vatne, Guro H.

AU - Kristiansen, Cecilie K.

AU - Hallin, Erik I.

AU - Skoda, Maximilian W.A.

AU - Bergmann, Ulrich

AU - Wacklin-Knecht, Hanna

AU - Jones, Nykola C.

AU - Hoffmann, Søren V.

AU - Kursula, Petri

PY - 2019

Y1 - 2019

N2 - 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.

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. 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.

U2 - 10.1371/journal.pone.0216833

DO - 10.1371/journal.pone.0216833

M3 - Article

C2 - 31173589

AN - SCOPUS:85067113554

VL - 14

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 6

M1 - e0216833

ER -