Human myelin proteolipid protein structure and lipid bilayer stacking

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dc.contributor.authorRuskamo, Sen_AU
dc.contributor.authorRaasakka, Aen_AU
dc.contributor.authorPedersen, JSen_AU
dc.contributor.authorMartel, Aen_AU
dc.contributor.authorŠkubník, Ken_AU
dc.contributor.authorDarwish, TAen_AU
dc.contributor.authorPorcar, Len_AU
dc.contributor.authorKursula, Pen_AU
dc.date.accessioned2023-11-20T23:07:42Zen_AU
dc.date.available2023-11-20T23:07:42Zen_AU
dc.date.issued2022-07-12en_AU
dc.date.statistics2022-09-02en_AU
dc.descriptionThe use of the facilities and expertise of the Biocenter Oulu Protein analysis, Structural Biology and EM core facilities is thankfully acknowledged. We further acknowledge the use of the Core Facility for Biophysics, Structural Biology, and Screening (BiSS) at the University of Bergen.en_AU
dc.description.abstractThe 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. © 2022 The Authors - Open Access under a Creative Commons Attribution 4.0.en_AU
dc.description.sponsorshipOpen Access funding provided by University of Oulu including Oulu University Hospital. This work was funded by the Academy of Finland, grant number 275225 and Jane and Aatos Erkko Foundation. Beamtime and user support at EMBL/DESY, SOLEIL, ILL and ISA are gratefully acknowledged. Travel to synchrotrons was supported by the European Union Horizon 2020 programs iNEXT (Grant 653706) and CALIPSOplus (Grant 730872). The National Deuteration Facility at ANSTO is partly funded by The National Collaborative Research Infrastructure Strategy (NCRIS), an Australian Government initiative. We acknowledge the cryo-electron microscopy and tomography core facility CEITEC MU of CIISB, Instruct-CZ Centre supported by MEYS CR (LM2018127).en_AU
dc.identifier.articlenumber419en_AU
dc.identifier.citationRuskamo, S., Raasakka, A., Pedersen, J. S., Martel, A., Škubník, K., Darwish, T., Porcar, L., Kursula, P. (2022). Human myelin proteolipid protein structure and lipid bilayer stacking. Cellular and Molecular Life Sciences, 79(8), 419. doi:10.1007/s00018-022-04428-6en_AU
dc.identifier.issn1420-9071en_AU
dc.identifier.issue8en_AU
dc.identifier.journaltitleCellular and Molecular Life Sciencesen_AU
dc.identifier.urihttps://doi.org/10.1007/s00018-022-04428-6en_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15212en_AU
dc.identifier.volume79en_AU
dc.language.isoenen_AU
dc.publisherSpringer Natureen_AU
dc.relation.urihttps://doi.org/10.1007/s00018-022-04428-6en_AU
dc.subjectMyelinen_AU
dc.subjectProteinsen_AU
dc.subjectMembranesen_AU
dc.subjectMembrane proteinsen_AU
dc.subjectSmall angle scatteringen_AU
dc.subjectAtomic force microscopyen_AU
dc.subjectNerve cellsen_AU
dc.subjectCentral nervous systemen_AU
dc.titleHuman myelin proteolipid protein structure and lipid bilayer stackingen_AU
dc.typeJournal Articleen_AU
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