Covalent modification of a protein by the linkage of an ADP-ribosyl moiety to the protein. The resulting product typically exhibits altered kinetic and/or regulatory properties. ADP-ribosyltransferases catalyze the trans fer of the ADP-ribosyl group of NAD+ to a protein acceptor, producing the modified protein and free nico-tinamide. The reaction scheme catalyzed by the cholera toxin A subunit and a rabbit muscle protein has been determined to be random1. The amino acyl residues that have been reported to have been modified in these reactions include a cysteinyl residue (e.g., via pertussis toxin2), an arginyl residue (via cholera toxin A), an asparaginyl residue (via botulinum toxin), and a modified histidyl residue (via diphtheria toxin). In addition, the subunit structure appears to have a role in substrate specificity13.

The widespread occurrence of ADP-ribosyltransfer-ases3-7 has generated considerable interest in assessing the role of ADP-ribosylation in cellular metabolism. Regulatory proteins associated with this modification event have also been identified. A small G-protein referred to as ARF (ADP-ribosylation factor) has been shown to enhance this covalent modification8-10. ARF actually represents a family of proteins, both cytosolic and membrane-bound. Interestingly, ARF has been shown to have a crucial role in vesicle transport from the Golgi1112. When ARF-GDP binds to a developing vesicle, a GDP|GTP exchange occurs, and the coatomer begins to form. After the vesicle pinches off, the GTP is hydrolyzed and the coatomer and ARF are released, allowing the vesicle to fuse with the target membrane.

1J. S.-A. Larew, J. E. Peterson & D. J. Graves (1991) J. Biol. Chem. 266, 52.

3M. D. Brightwell, C. E. Leech, M. K. O'Farrell, W. J. D. Whish &

S. Shall (1975) Biochem. J. 147, 119. 4J. Moss, S. J. Stanley & P. A. Watkins (1980) J. Biol. Chem. 255, 5838.

5J. Moss & S. J. Stanley (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 4809.

6J. Moss & S. J. Stanley (1981) J. Biol. Chem. 256, 7830. 7G. Soman, J. R. Mickelson, C. F. Louis & D. J. Graves (1984) Biochem. Biophys. Res. Commun. 120, 973. 8R. A. Kahn & A. G. Gilman (1986) J. Biol. Chem. 261, 7906. 9L. Monoco, J. J. Murtaugh, K. B. Newman, S.-C. Tsai, J. Moss &

M. Vaughn (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 2206. 10M. Tsuchiya, S. R. Price, M. S. Nightingale, J. Moss & M. Vaughn

(1989) Biochemistry 28, 9668. 11J. E. Rothman (1994) Nature 372, 55. 12J. E. Rothman and L. Orci (1996) Sci. Amer. 274 (3), 70. 13D. J. Graves, B. L. Martin & J. H. Wang (1994) Co- and Posttrans-

lational Modification of Proteins, Oxford Univ. Press, New York. Selected entries from Methods in Enzymology [vol, page(s)]: By bacterial toxin, 235, 617-632; by cholera toxin [catalysis, 237, 45; assay, 235, 642-647; G protein as subunit, 237, 48]; by pertussis toxin, 237, 24-26, 71, 132-133; G-protein subunits, 237, 236238; time-course of transducin ADP-ribosylation, 237, 77-79, 91, 93-94.

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