The myelin sheath is of fundamental importance for transmitting stimuli in the brain. It surrounds the axons of neurons and accelerates the electrical signals along the axons. As a major component of myelin in the peripheral nervous system, the transmembrane glycoprotein protein zero (P0) plays a crucial role in stabilizing the myelin sheath. Through its extracellular domain, P0 promotes the adhesion of adjacent membranes, thereby contributing to the formation of a compact myelin layer. The cytoplasmic tail of myelin protein zero (P0ct) is an intrinsically disordered domain. Mutations and modifications in the P0ct region are associated with specific neurological disorders, such as Charcot-Marie-Tooth disease. This study investigates the interaction of P0ct-wt and the D224Y variant with myelin-like lipid monolayers and individual myelin lipids at the air-water interface. Measuring adsorption isotherms on Langmuir film balances, and calculating the maximum insertion pressures (MIPs) clearly demonstrate the ability of P0ct to interact with and incorporate into negatively charged lipid monolayers such as phosphatidylinositol (PI). Despite its intrinsic disorder, AlphaFold predicts the presence of partially folded secondary structure elements in P0ct, primarily alpha-helices. In our study, we verify the predictions made by AlphaFold using infrared reflection-absorption-spectroscopy (IRRAS). Hereby, the protein-lipid surface interactions as well as the secondary structure of the adsorbed proteins can be determined. Furthermore, we investigate conceivable changes in P0ct-lipid interactions resulting from an altered lipid monolayer. Our study contributes to the basic understanding of the function of P0 in the myelin sheath and the specific role of each individual myelin lipid.
Hingst et al. (Sun,) studied this question.