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PreprintCited by 1Lipid Membrane Structure and BehaviorProtein Structure and DynamicsMultiple Sclerosis Research Studies

Human myelin proteolipid protein structure and lipid bilayer stacking

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Ruskamo, Salla, Raasakka, Arne, Pedersen, Jan Skov, Martel, Anne, Škubník, Karel, Darwish, Tamim, Porcar, Lionel, Kursula, Petri·2022·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2022.03.14.484199

Preprint — published as 10.1007/s00018-022-04428-6

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Abstract

The myelin sheath is an essential, multilayered membrane structure that insulates axons, enabling the rapid transmission of nerve impulses. The tetraspan myelin proteolipid protein (PLP) is the most abundant protein of compact myelin in the central nervous system (CNS). The integral membrane protein PLP adheres myelin membranes together and enhances the compaction of myelin, having a fundamental role in myelin stability and axonal support. PLP is linked to severe CNS neuropathies, including inherited Pelizaeus-Merzbacher disease and spastic paraplegia type 2, as well as multiple sclerosis. Nevertheless, the structure, lipid interaction properties, and membrane organization mechanisms of PLP have remained unidentified. We expressed, purified, and structurally characterized human PLP and its shorter isoform DM20. Synchrotron radiation circular dichroism spectroscopy and small-angle X-ray and neutron scattering revealed a dimeric, α-helical conformation for both PLP and DM20 in detergent complexes, and pinpoint structural variations between the isoforms and their influence on protein function. In phosphatidylcholine membranes, reconstituted PLP and DM20 spontaneously induced formation of multilamellar myelin-like membrane assemblies. Cholesterol and sphingomyelin enhanced the membrane organization but were not crucial for membrane stacking. Electron cryomicroscopy, atomic force microscopy, and X-ray diffraction experiments for membrane-embedded PLP/DM20 illustrated effective membrane stacking and ordered organization of membrane assemblies with a repeat distance in line with CNS myelin. Our results shed light on the 3D structure of myelin PLP and DM20, their structure-function differences, as well as fundamental protein-lipid interplay in CNS compact myelin.

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Authors
Ruskamo, S., Raasakka, A., Pedersen, J. S., Martel, A., Škubník, K., Darwish, T., Porcar, L., & Kursula, P.
Affiliations
  • University of Oulu (FI)
  • University of Bergen (NO)
  • Aarhus University (DK)
  • Institut Laue-Langevin (FR)
  • Central European Institute of Technology – Masaryk University (CZ)
  • Australian Nuclear Science and Technology Organisation (AU)
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2022-03-14
DOI
10.1101/2022.03.14.484199
OpenAlex
W4220724308
Cited by
1
References
4
Citations by year
2025: 1
Type
posted content
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Desy Publications Database (Deutsches Elektronen-Synchrotron DESY) (submittedVersion, other-oa)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
Funders
  • Australian Nuclear Science and Technology Organisation
  • Australian Government
  • CALIPSOplus (730872, Grant 730872)
  • European Commission (730872, 653706, HORIZON2020)
  • Ministerstvo Školství, Mládeže a Tělovýchovy (LM2018127)
  • Academy of Finland (275225, 730872)
  • Jane ja Aatos Erkon Säätiö
  • Universitetet i Bergen
  • Central European Institute of Technology (LM2018127)
  • Deutsches Elektronen-Synchrotron (653706, 730872)
  • Biocenter, University of Oulu
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
Keywords
myelin proteolipid protein, DM20, compact myelin, myelin sheath, protein-lipid interactions, protein structure, phosphatidylcholine membranes, cholesterol, sphingomyelin, Pelizaeus-Merzbacher disease, multiple sclerosis

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