The major myelin protein expressed by the peripheral nervous system Schwann cells is protein zero (P0), which represents 50 % of the total protein content in myelin. This 30-kDa integral membrane protein consists of an immunoglobulin (Ig)-like domain, a transmembrane helix, and a 69-residue C-terminal cytoplasmic tail (P0ct). The basic residues in P0ct contribute to the tight packing of myelin lipid bilayers, and alterations in the tail affect how P0 functions as an adhesion molecule necessary for the stability of compact myelin. Several neurodegenerative neuropathies are related to P0, including the more common Charcot-Marie-Tooth disease (CMT) and Dejerine-Sottas syndrome (DSS) as well as rare cases of motor and sensory polyneuropathy. We found that high P0ct concentrations affected the membrane properties of bicelles and induced a lamellar-to-inverted hexagonal phase transition, which caused bicelles to fuse into long, protein-containing filament-like structures. These structures likely reflect the formation of semicrystalline lipid domains with potential relevance for myelination. Not only is P0ct important for stacking lipid membranes, but time-lapse fluorescence microscopy also shows that it might affect membrane properties during myelination. We further describe recombinant production and low-resolution structural characterisation of full-length human P0. Our findings shed light on P0ct effects on membrane properties, and with the successful purification of full-length P0, we have new tools to study the role of P0 in myelin formation and maintenance in vitro. 

The cytoplasmic tail of myelin protein zero induces morphological changes in lipid membranes

Abstract The major myelin protein expressed by the peripheral nervous system Schwann cells is protein zero (P0), representing 50% of the total protein content in myelin. This 30-kDa integral membrane protein consists of an immunoglobulin (Ig)-like domain, a transmembrane helix, and a 69-residue C-terminal cytoplasmic tail (P0ct). The basic residues in P0ct contribute to the tight packing of the myelin lipid bilayers, and alterations in the tail affect how P0 functions as an adhesion molecule necessary for the stability of compact myelin. Several neurodegenerative neuropathies are related to P0, including the more common Charcot-Marie-Tooth disease (CMT) and Dejerine-Sottas syndrome (DSS), but also rare cases of motor and sensory polyneuropathy. We find that high P0ct concentrations affect the membrane properties of bicelles and induce a lamellar-to-inverted hexagonal phase transition, which causes the bicelles to fuse into long, protein-containing filament-like structures. These structures likely reflect the formation of semi-crystalline lipid domains of potential relevance for myelination. Not only is P0ct important for stacking lipid membranes, but time-lapse fluorescence microscopy shows that it might affect membrane properties during myelination. We further describe recombinant production and low-resolution structural characterization of full-length human P0. Our findings shed light on P0ct effects on membrane properties, and with successful purification of full-length P0, we have new tools to study in vitro the role P0 has in myelin formation and maintenance. 

pdf/the-cytoplasmic-tail-of-myelin-protein-zero-induces-1xok4z3ql5.pdf

Myelin is a proteolipid membrane multilayer held together by a set of proteins. The proper formation and function of the myelin sheath relies on the coordinated action of several key myelin proteins. Research exploring how proteins from the peripheral myelin cytoplasmic apposition - myelin basic protein (MBP), the cytoplasmic tail of myelin protein zero (P0ct), and peripheral myelin protein 2 (P2) - interact with each other and with myelin-like membranes was conducted using various techniques, such as small-angle X-ray diffraction (SAXD), differential scanning calorimetry (DSC), surface plasmon resonance (SPR), as well as electron and live epifluorescence microscopy. DSC revealed changes in lipid interactions depending on the protein combination, with MBP and P0ct binding more tightly to lipid membranes than P2, resulting in altered membrane fluidity and stability. These results were supported by SPR, which indicated that the myelin proteins may compete for membrane surface binding. Analysis of the Bragg peaks induced by the myelin proteins in lipidic environments showed both lamellar and non-lamellar phases in protein-lipid complexes. The results indicate both synergy and competition between the three main proteins residing in the PNS myelin major dense line. Furthermore, the observed direct effects of myelin proteins on lipid membrane properties may be relevant to their function in myelinating cells. 

On the synergy between myelin proteins P0, MBP, and P2 in peripheral nerve major dense line formation

In this study, the interplay among the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) as a model membrane, the nonsteroidal anti-inflammatory drug naproxen, and the saponin β-aescin are investigated. The naproxen amount was fixed to 10 mol%, and the saponin amount varies from 0.0 to 1.0 mol%. Both substances are common ingredients in pharmaceutics; therefore, it is important to obtain deeper knowledge of their impact on lipid membranes. The size and properties of the DMPC model membrane upon naproxen and aescin addition were characterized with differential scanning calorimetry (DSC), small- and wide-angle X-ray scattering (SAXS, WAXS), and photon correlation spectroscopy (PCS) in a temperature-dependent study. The interaction of all substances was dependent on the lipid phase state, which itself depends on the lipid’s main phase transition temperature Tm. The incorporation of naproxen and aescin distorted the lipid membrane structure and lowers Tm. Below Tm, the DMPC–naproxen–aescin mixtures showed a vesicle structure, and the insertion of naproxen and aescin influenced neither the lipid chain–chain correlation distance nor the membrane thickness. Above Tm, the insertion of both molecules instead induced the formation of correlated bilayers and a decrease in the chain–chain correlation distance. The presented data clearly confirm the interaction of naproxen and aescin with DMPC model membranes. Moreover, the incorporation of both additives into the model membranes is evidenced.

/pdf/interactions-between-dmpc-model-membranes-the-drug-naproxen-s9263n2s.pdf

Interactions between DMPC Model Membranes, the Drug Naproxen, and the Saponin β-Aescin

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Interactions between DMPC Model Membranes, the Drug Naproxen, and the Saponin β-Aescin