Sep 21, 2005

Autocatalytic cleavage of myelin basic protein: an alternative to molecular mimicry

Biochemistry
Cheryl A D'SouzaMario A Moscarello

Abstract

Although multiple sclerosis (MS) is thought to be an autoimmune disease, the mechanisms by which immunodominant epitopes are generated and lymphocytes are activated are not known. Here, myelin basic protein-component 1 (MBP-C1) from MS tissue was shown to undergo autocatalytic cleavage at slightly alkaline pH. Importantly, one of the major peptides released contained the immunodominant epitope 84-89. Interestingly, MBP isolated from MS patients showed a faster time course of cleavage and a more robust release of epitope 84-89 than MBP isolated from normal individuals. The cleavage reaction was not inhibited by protease inhibitors, except for phenylmethanesulfonyl fluoride (PMSF), a serine protease inhibitor. Since PMSF inhibition suggested a role for a serine residue in the cleavage, we labeled myelin 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. Since this peptide contained a single serine residue, we concluded it to be the active serine. The importance of this cleavage mechanism is that it provides for a ready source of the immunodominant peptide for sensitization of T-cells. It i...Continue Reading

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Mentioned in this Paper

Protease Inhibitors [MoA]
T-Lymphocyte
Lymphocytes as Percentage of Blood Leukocytes (Lab Test)
Antigens, Immunodominant
Floropryl
Isoflurophate
Proteins, Recombinant DNA
Serine Proteinase Inhibitors
Cytokinesis of the Fertilized Ovum
Protease inhibitors, direct acting antivirals

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