title: Substitution of lysine for arginine at position 42 of human transforming growth factor-alpha eliminates biological activity without changing internal disulfide bonds.
abstract: Transforming growth factor-alpha (TGF-alpha) is a growth-promoting protein that binds to the epidermal growth factor (EGF) receptor. To identify critical residues that govern TGF-alpha-EGF receptor binding, we prepared site-specific substitution mutants of TGF-alpha. Mutant proteins were tested in receptor-binding and mitogenesis assays. Semiconservative substitutions at positions 4, 12, 18, and 45 decreased biological activity 2.1- to 14-fold. The conservative substitution of lysine for arginine at position 42 completely eliminated biological activity. Amino acid composition analysis of proteolytic fragments from TGF-alpha and the Lys-42 mutant indicated that these proteins contained the same disulfide bonds. These studies suggest that arginine 42 may be a contact point for TGF-alpha-EGF receptor interaction.
authors.affiliation: Department of Cancer Research, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: D
authors.initials: D
authors.lastname: Defeo-Jones
authors.forename: J Y
authors.initials: JY
authors.lastname: Tai
authors.forename: G A
authors.initials: GA
authors.lastname: Vuocolo
authors.forename: R J
authors.initials: RJ
authors.lastname: Wegrzyn
authors.forename: T L
authors.initials: TL
authors.lastname: Schofield
authors.forename: M W
authors.initials: MW
authors.lastname: Riemen
authors.forename: A
authors.initials: A
authors.lastname: Oliff
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine; D001665:Binding Sites; D004220:Disulfides; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008239:Lysine; D008934:Mitogens; D008969:Molecular Sequence Data; D015291:Transforming Growth Factors / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004220:Disulfides; D008934:Mitogens; D015291:Transforming Growth Factors; D001120:Arginine; D066246:ErbB Receptors; D008239:Lysine