Human Peripheral Myelin Protein 2 and Charcot-Marie-Tooth Disease or Structural Missense Variants Show Different Binding to Myelin-Like Lipid Monolayers.

The peripheral myelin protein P2 (also known as PMP2/FABP8) has two basic functions in vivo: the transport of fatty acids within the cell to the target compartments and the adhesion of lipid bilayers in the peripheral nervous system myelin to each other. In this work, we focus on the membrane-binding properties of P2 and its Charcot-Marie-Tooth disease variants. Experiments were carried out on lipid monolayers at the air-water interface as a membrane model system, with the lipid composition of the cytoplasmic leaflet of myelin. Our study provides quantitative data on the membrane affinity of P2 and its disease-linked or structure-based missense variants toward the native lipid membrane and shows affinity differences due to single P2 point mutations. Phospholipid monolayer surface pressure measurements are supported by epifluorescence microscopy, which not only shows the adhesive property of all P2 variants but also the complex cross-linking property of the wild-type P2. An analysis of transcriptomics databases confirms expression of P2 in human, but not mouse, central nervous system nonneuronal cells. Taken together, our work further confirms the role of P2 in binding myelin-like lipid membranes as well as its direct effects on lipid membrane properties.