Fig. 8

Modeling the lysosomal hydrolysis of a glycolipid. Two lipids (cholesterol-like and GM2-like molecules) were included as membrane-associated cargoes in the simulation. The lipids were loaded in newly formed RabA endosomes, mimicking the uptake from a plasma membrane domain enriched in these molecules. Cholesterol was given affinity for RabA and RabB domains and GM2 for RabD structures. Cholesterol was processed by a reaction programmed in COPASI that depends on the presence of RabD domains. GM2 was digested by a reaction programmed in COPASI that requires HexA, low pH, and low cholesterol. a Cholesterol distribution among different Rab domains along the simulation. Notice that after a few minutes, the lipid formed a gradient in the endocytic route with decreasing concentrations from RabA to RabD structures. b Same as in a, but for GM2. After a transient increase in RabD endosomes, GM2 was maintained at low concentrations in these late endosome/lysosomal structures. Like for cholesterol, a gradient was formed, decreasing from RabA to RabD endosomes. Notice, however, that part of the lipid recycled back to the surface. c When the cholesterol was not removed from RabD structures (the reaction was inhibited in COPASI), the lipid accumulated in RabD endosomes. d GM2 hydrolysis was inhibited by the high cholesterol levels in RabD endosomes; hence, the ganglioside content increased with time in late endosomes. Data on panel a to d correspond to the average of 10 independent simulations