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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 and Wacklin-Knecht, Hanna LU orcid , et al. (2019) In PLoS ONE 14(6).
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-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.... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
14
issue
6
article number
e0216833
publisher
Public Library of Science (PLoS)
external identifiers
  • scopus:85067113554
  • pmid:31173589
ISSN
1932-6203
DOI
10.1371/journal.pone.0216833
language
English
LU publication?
yes
id
a5a290c7-da14-4dcc-8922-485972f18eb9
date added to LUP
2019-07-01 09:22:55
date last changed
2024-07-25 01:33:06
@article{a5a290c7-da14-4dcc-8922-485972f18eb9,
  abstract     = {{<p>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.</p>}},
  author       = {{Raasakka, Arne and Ruskamo, Salla and Barker, Robert and Krokengen, Oda C. and Vatne, Guro H. and Kristiansen, Cecilie K. and Hallin, Erik I. and Skoda, Maximilian W.A. and Bergmann, Ulrich and Wacklin-Knecht, Hanna and Jones, Nykola C. and Hoffmann, Søren V. and Kursula, Petri}},
  issn         = {{1932-6203}},
  language     = {{eng}},
  number       = {{6}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS ONE}},
  title        = {{Neuropathy-related mutations alter the membrane binding properties of the human myelin protein P0 cytoplasmic tail}},
  url          = {{http://dx.doi.org/10.1371/journal.pone.0216833}},
  doi          = {{10.1371/journal.pone.0216833}},
  volume       = {{14}},
  year         = {{2019}},
}