Autocatalytic Cleavage of Myelin Basic Protein: An Alternative to Molecular Mimicry

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• 作者：Cheryl A. D'Souza ; D. Denise Wood ; Yi-Min She ; and Mario A. Moscarello
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：September 27, 2005
• 年：2005
• 卷：44
• 期：38
• 页码：12905 - 12913
• 全文大小：5421K
• 年卷期：v.44,no.38(September 27, 2005)
• ISSN：1520-4995

文摘

Although multiple sclerosis (MS) is thought to be an autoimmune disease, the mechanisms bywhich immunodominant epitopes are generated and lymphocytes are activated are not known. Here, myelinbasic protein-component 1 (MBP-C1) from MS tissue was shown to undergo autocatalytic cleavage atslightly alkaline pH. Importantly, one of the major peptides released contained the immunodominant epitope84-89. Interestingly, MBP isolated from MS patients showed a faster time course of cleavage and amore robust release of epitope 84-89 than MBP isolated from normal individuals. The cleavage reactionwas not inhibited by protease inhibitors, except for phenylmethanesulfonyl fluoride (PMSF), a serineprotease inhibitor. Since PMSF inhibition suggested a role for a serine residue in the cleavage, we labeledmyelin basic protein with diisopropyl fluorophosphate (DFP), known to bind active site serine residues.Mass spectrometry was used to identify the labeled peptide, which consisted of residues 140-152. Sincethis peptide contained a single serine residue, we concluded it to be the active serine. The importance ofthis cleavage mechanism is that it provides for a ready source of the immunodominant peptide forsensitization of T-cells. It is not necessary to invoke other mechanisms such as molecular mimicry.