Dual mechanisms involved in the development of diverse biological activities of islet-activating protein, (pertussis toxin) as revealed by chemical modification of the toxin molecule.
Islet-activating protein (IAP) pertussis toxin is composed of an A-protomer and a B-oligomer. The B-oligomer binds to the mammalian cell surface via the constituent two dimers (D1 and D2). IAP displays several biological effects including lymphocytosis-promoting, histamine-sensitizing, adjuvant, vascular permeability increasing and mitogenic activities. These activities were markedly suppressed by acetamidination or reductive methylation of the lysine residues in the D2 molecule. The free amino groups of the lysine residues thus play an essential role in the binding of D2 to cells which is responsible for development of these biological activities. In sharp contrast, the islet-activating activity was not prevented by the same chemical modification of the IAP molecule. This activity results from ADP-ribosylation catalyzed by the A-protomer which is rendered accessible to the intramembrane substrate protein thanks to the B-oligomer binding to the cell surface. Free amino groups of the lysine residues played no role in this type of binding of the B-oligomer via D1. Thus, at least two mechanisms underly the diverse biological activities of pertussis toxin.
K
K
Nogimori
M
M
Tamura
T
T
Nakamura
M
M
Yajima
K
K
Ito
M
M
Ui
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D006636:Histamine Release / Q000187:drug effects; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008218:Lymphocytosis / Q000139:chemically induced; D008745:Methylation; D051379:Mice; D008934:Mitogens; D037342:Pertussis Toxin; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D010566:Virulence Factors, Bordetella / Q000378:metabolism / Q000494:pharmacology*
D007328:Insulin; D008934:Mitogens; D010566:Virulence Factors, Bordetella; D000246:Adenosine Diphosphate Ribose; D037342:Pertussis Toxin