How does membrane composition modulate cholesterol carrier protein NPC2?

Niemann-Pick Protein C2 (NPC2) is a small soluble protein, which facilitates the endosomal/lysosomal cholesterol efflux, a vital step in cholesterol metabolism. Mutations in NPC2 causes Niemann-Pick C disease, in which lipid accumulation causes neuronal degeneration and early death. Specific lipids found in the lysosome/late endosome affect the efficiency of NPC2-mediated cholesterol transport, but the molecular mechanism of this activity modulation remains elusive. We performed atomistic molecular dynamics simulations and free energy calculations to investigate the effect of relevant lipids on NPC2-membrane binding. We characterize a mechanism for membrane association and two distinct membrane binding modes of NPC2: a “cholesterol-exchange mode” and an “idle mode”. We systematically show that i) anionic lipids are necessary and sufficient for unspecific membrane association; ii) a unique anionic lysosomal/endosomal lipid, BMP, however, is required for the “cholesterol exchange mode”; and iii) sphingomyelin (SM) counteracts BMP by favoring the “idle mode”. Our findings suggest that BMP and SM modulates NPC2-mediated cholesterol transport by favoring one of the two binding modes.