A Single Native Ganglioside GM(1)-Binding Site Is Sufficient for Cholera Toxin To Bind to Cells and Complete the Intoxication Pathway

Jobling, Michael G.; Yang, ZhiJie; Kam, Wendy R.; Lencer, Wayne I.; Holmes, Randall K.

Another way that multivalent binding to GM 1 might affect CT function would be through reorganization of membrane structure and function induced by scaffolding GM 1 into ceramide-based nanodomains, as suggested by studies in vitro and in vivo (14, 15, (30) (31) (32) (33) . Significantly, studies of the closely related AB 5 subunit Shiga toxin show that multivalent binding to the glycosphingolipid GB3 spontaneously induces high-curvature membrane tubules by coupling the toxin-lipid complex to membrane shape (31) . Multivalent binding of CT to GM 1 in model membranes also induces spontaneous membrane curvature, implying a similar coupling of the toxin-glycosphingolipid complex formation to membrane shape (32, 34, 35) . This could allow partitioning of the CT-GM 1 complex into highly curved sorting tubules of the sorting endosome, which is required for retrograde transport, and explain why the toxins with more than 1 GM 1 binding site are more potent in intoxication. It is also possible that multivalent binding to GM 1 may be needed to activate intracellular signaling pathways that enhance uptake and trafficking, as for Shiga toxin (36) .