Membrane topology of PLP in CNS myelin: Evaluation of models

Abstract

Three new models for proteolipid protein (PLP) topology in the myelin membrane have been proposed—the 4-helix N_in and N_out models of Popot (J. Membr. Biol. 120:233–246), and the model of Weimbs and Stoffel (Biochemistry 31:12289–12296). Unlike the earlier models proposed by Laursen (Proc. Natl. Acad. Sci. USA 81:2912–2916), Stoffel (Proc. Natl. Acad. Sci. USA. 81:5012–5016) and Hudson (J. Cell Biol. 109:717–727), the four hydrophobic clusters are all assigned as membrane-spanning domains. ThePopot-N _in andWeimbs models, which are similar to theLaursen model, both assign the positively-charged domain, which is deleted from the DM20 transcript of PLP, to the cytoplasmic surface, while thePopot-N _out model, similar to theStoffel andHudson models, assigns this sequence to the extracellular surface. Our calculations of membrane surface charge shows that the disposition of this basic domain greatly influences membrane interactions, by shifting the equilibrium myelin period to alkaline pH due to the electrostatic repulsion force at the extracellular apposition. In theLaursen, Popot-N _in andWeimbs models, the onset of swelling was calculated to be at lower pH than in theStoffel, Hudson andPopot-N _out models, and lower than that observed experimentally with mouse optic nerve myelin. The absolute electron density profile of the myelin membrane that is derived from the x-ray diffraction patterns shows similar density levels at its cytoplasmic and extracellular surfaces. By contrast, the electron density profile calculated from a chemical model that includes lipids plus myelin basic protein (but not PLP) shows a higher density at the cytoplasmic than at the extracellular side. Among the proposed models of PLP, theHudson model has more residues at the extracellular than at the cytoplasmic side, and consequently gives a symmetric electron density distribution at the two membrane surfaces when included with the myelin lipids and MBP.