Myelin basic protein (MBP) is one of the major protein components of the CNS myelin sheath. The protein is closely associated with the inner folds of the myelin membrane where it provides stability to the multilamellar structure. Autoimmune responses to MBP have been implicated in the demyelinating diseases experimental allergic encephalomyelitis and multiple sclerosis. The exact mechanism of the interaction between MBP and the myelin membrane is not well understood. It has been suggested, however, that the methylation of the protein on Arginine-107 is an important aspect of the microscopic interaction mechanism. This residue is methylated by reaction with S-adenosylmethionine (SAM), although the enzyme catalyzing this methylation has not been purified. In order to more completely understand the mechanism of the myelin-MBP interaction, we propose to isolate and purify the enzyme system responsible for the methylation reaction. This enzyme will be characterized kinetically and the mechanism of the methylation reaction will be investigated. The role of the methylated arginine in the myelin-MBP interaction will be investigated with special emphasis on the suggestion that a deficiency in methylation may be associated with increased susceptibility to demyelinating diseases. The mechanism of lamellae destabilization during the phagocytosis of myelin will be investigated with special emphasis on the role of lysosomal pH gradients in primary and """"""""bystander"""""""" demyelination. This work will directly contribute to our understanding of the chemical and kinetic mechansisms of methyltransferase enzymes, the physiological consequences of the methylation of MBP and will approach an understanding of the mechanisms of cell-mediated myelin degeneration in multiple sclerosis and similar demyelinating diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Modified Research Career Development Award (K04)
Project #
5K04NS000775-05
Application #
3074685
Study Section
Physical Biochemistry Study Section (PB)
Project Start
1983-04-01
Project End
1988-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
5
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Schools of Arts and Sciences
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Young, P R; Karunatilake, C (1992) Bovine brain cathepsin D: inhibition by pepstatin and binding to concanavalin A. Int J Biochem 24:229-33
Young, P R; Synder, W R; McMahon, R F (1992) Inhibition of Clostridium perfringens phospholipase C by ammonium and sulfonium dications. Biochim Biophys Acta 1121:297-300
Young, P R; Snyder, W R; McMahon, R F (1991) Kinetic mechanism of Clostridium perfringens phospholipase C. Hydrolysis of a thiophosphate analogue of lysophosphatidylcholine. Biochem J 280 ( Pt 2):407-10
Young, P R; Karanutilake, C; Zygas, A P (1991) Binding of cathepsin D to the mannose receptor on rat peritoneal macrophages. Biochim Biophys Acta 1095:1-4
Young, P R; Snyder, W R; McMahon, R F (1991) Inhibition of the Clostridium perfringens phospholipase C hydrolysis of a thiophosphate analog of lysophosphatidylcholine by micelle-bound ammonium and sulfonium cations. Lipids 26:957-9
Young, P R; Briedis, A V (1990) Binding of inhibitors to the major glutathione S-transferase from bovine brain. Competitive binding between bilirubin and glutathione. Biochim Biophys Acta 1038:114-8
Young, P R; Briedis, A V (1989) Purification and kinetic mechanism of the major glutathione S-transferase from bovine brain. Biochem J 257:541-8
Young, P R; Waickus, C M (1988) Purification and kinetic mechanism of S-adenosylmethionine: myelin basic protein methyltransferase from bovine brain. Biochem J 250:221-6
Young, P R; Snyder, W R; Vacante, D A et al. (1988) The acid instability of myelin. A model for myelin degeneration in multiple sclerosis. Med Hypotheses 26:31-7
Young, P R; Briedis, A V (1988) Kinetics and mechanism of the glutathione-dependent reduction of dehydromethionine. Biochim Biophys Acta 967:318-21

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