Biophysics of ceramide signaling: interaction with proteins and phase transition of membranes

Ceramides have been implied in intracellular signal transduction systems re gulating cellular differentiation, activation, survival and apoptosis and t hus appear capable of changing the life style of virtually any cell type. C eramide belongs to the group of sphingosine-based lipid second messenger mo lecules that are critically involved in the regulation of diverse cellular responses to exogenous stimuli. The emerging picture suggests that coupling of ceramide to specific signaling cascades is both stimulus and cell-type specific and depends on the subcellular topology of its production. However , little is understood about the molecular mode of ceramide action. In part icular, in lieu of a defined ceramide binding motif it is not clear how cer amide would directly interact with putative target signaling proteins. This article proposes two modes of ceramide action. First, a protruding alkyl c hain of ceramide may interact with a hydrophobic cavity of a signaling prot ein providing a lipid anchor to attach proteins to membranes. Second, the g eneration of ceramide generally increases the volume of hydrocarbon chains within the lipid bilayer thereby enhancing its propensity of to form a hexa gonal II phase (Hex EI). Besides the generation of a hydrophobic interactio n site for proteins local hexagonal phase II formation can also change the membrane fluidity and permeability, which may impinge on membrane fusion pr ocesses, solubilization of detergent-resistent signaling rafts, or membrane receptor internalization. Thus, ceramide production by sphingomyelinases ( SMase) can play a pivotal signaling role through direct interaction with si gnaling proteins or through facilitating the formation and trafficking of s ignal transduction complexes. (C) 1999 Elsevier Science Ireland Ltd. All ri ghts reserved.