Predicted Folding of β‐Structure in Myelin Basic Protein

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Abstract
Predictions of myelin basic protein [MBP] secondary structure have not previously considered a major role for .beta.-structure in the organization of the native molecule because optical rotatory dispersion and circular dichroism studies have provided little, if any, evidence for the .beta.-structure; in addition to this a polycationic protein is generally considered to resist folding into a compact structure. The Chou-Fasman, Lim and Robson algorithms identify a total of 5 .beta.-strands in the amino acid sequence. Four of these hydrophobic amino acid sequences (37-45, 87-95, 110-118, and 150-158) could form a hairpin intermediate that initiates folding of a Greek-key-type .beta.-structure. A 2nd fold on the more hydrophobic side, with the addition of a strand from the N-terminus (residues 13-21), would complete the 5-stranded antiparallel .beta.-sheet. A unique strand alignment can be predicted by phasing the hydrophobic residues. The unusual triproline sequence of MBP (100-102) is enclosed in the 14-residue hairpin loop. If these prolines are in the trans conformation, models show that a reverse turn could occur at residues 102-105 (Pro-Ser-Gln-Gly). Algorithms do not agree on the prediction of .alpha.-helices, but each of the 2 large loops could accommodate an .alpha.-helix. MBP is known to be phosphorylated in vivo on as many as 5 Ser/Thr residues. Phosphorylation might alter the dynamics of folding if the nascent polypeptide were phosphorylated in the cytoplasm. In particular, phosphorylation of Thr-99 could neutralize cationic residues Lys-106 and Arg-108 within the hairpin loop. The methylation of Arg-108 might stabilize the hairpin loop structure through hydrophobic interaction with the side chain of Pro-97. The cationic side chains of arginine and lysine residues located on the faces of the .beta.-sheet (Arg-43, Arg-114, Lys-13, Lys-92, Lys-153, and Lys-156) could provide sites for interaction with phospholipids and other anionic structures on the surface of the myelin lipid bilayer in human and bovine MBP.