Abstract:Rapid cleavage of bovine and guinea pig myelin basic proteins by pepsin at pH 6.0 is limited to the Phe‐Phe bond in the middle of the molecule. In the rabbit protein, however, rapid cleavages occur elsewhere in addition to the Phe87‐Phe88bond in regions in which there are amino acid substitutions. Rapid cleavage occurs at the Leu151‐Phe152bond, at which Ile‐151 has been replaced by Leu, the residue that actually contributes the scissile bond. Rapid cleavages occur at the Phe44‐Phe45and Leu109‐Ser110bonds, which in the bovine and guinea pig proteins are relatively resistant under the experimental conditions (pH 6.0). The increased susceptibility of these bonds in the rabbit protein appears to be related to the replacement of Gly‐46 by Ser and the change in the sequence immediately NH2‐terminal to Leu‐109, from Leu‐Ser to Thr‐Val. These cleavages of the rabbit protein at the four very susceptible bonds have permitted us to isolate peptides (1‐44), (45‐87), (88‐109), (110‐151), and (152‐168) in high yield. We have also isolated peptides (88‐151), (1‐14), and (15‐44) in low yield; the latter two result from limited cleavage at the relatively resistant Tyr14Leu15bond. Peptide (88‐109) has been chromatographically resolved into species differing in the degree of methylation of Arg‐105; this resolution is thought to result from differences in hydrogen