A General Model of the P2 Protein of Peripheral Nervous System Myelin Based on Secondary Structure Predictions, Tertiary Folding Principles, and Experimental Observations

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Abstract
The amino acid sequence of the P2 protein of peripheral myelin was analyzed with regard to regions of probable α-helix, β-structure, β-turn, and unordered conformation by means of several algorithms commonly used to predict secondary structure in proteins. Because of the high β-sheet content and virtual absence of α-helix shown by the circular dichroic spectra of the protein, a bias was introduced into the algorithms to favor the β-structure over the α-helical conformation. In order to define those β-sheet residues that could lie on the external hydrophilic surface of the protein and those that could lie in its hydrophobic interior, the predicted β-strands were examined for charged and uncharged amino acids located at alternating positions in the sequence. The sequential β-strands in the predicted secondary structure were then ordered into β-sheets and aligned according to generally accepted tertiary folding principles and certain chemical properties peculiar to the P2 protein. The general model of the P2 protein that emerged was a “Greek key”β-barrel, consisting of eight antiparallel β-strands with a two-stranded ribbon of antiparallel β-structure emerging from one end. The model has an uncharged, hydrophobic core and a highly hydrophilic surface. The two Cys residues, which form a disulfide, occur in a loop connecting two adjacent antiparallel strands. Two hydrophilic loops, each containing a cluster of acidic residues and a single Phe, protrude from one end of the molecule. The general model is consistent with many of the properties of the actual protein, including the relatively weak nature of its association with myelin lipids and the positions of amino acid substitutions. Alternative β-strand orderings yield three specific models having different interstrand connections across the barrel ends.