The effect of membrane lipid composition on endosomal cholesterol transport

Bis(monoacylglycero)phosphate (BMP) is a phospholipid only found in lysosomes and late endosomes.

Bis(monoacylglycero)-phosphate (BMP) is a phospholipid only found in lysosomes and late endosomes.

Niemann-Pick type C is a genetic disorder caused by mutations in NPC1 and NPC2 genes. The proteins coded by these genes work as a team to transfer cholesterol from lysosomes, the waste disposal systems of the cell. Malfunction of either of these proteins causes accumulation of cholesterol and other lipids. Individuals affected suffer from difficulty coordinating movements, poor muscle tone, liver disease, lung disease, and problems with basically all organs. Niemann-Pick disease is fatal and patients usually die before age of five. Also lysosomal membrane lipids have some role in cholesterol transportation. In this project that role is studied using molecular dynamics. This project is the topic of my masters thesis, which should be finished soon.

Structure and function of NPC1 and NPC2 has been studied a lot. In a proposed “hydrofobic hand-off” -model the soluble NPC2 picks cholesterol from the lysosome lumen, and transports it to NPC1, which is a lysosomal membrane protein. The exact mechanism how NP2 picks the cholesterol is not fully understood. Abdul Hammed et al. have studied the effect of NPC2 and some membrane lipids (sphingomyelin (PSM), ceramide (CER) and bis(monoacylglycero)phosphate (BMP)) on cholesterol transfer and membrane fusion [1]. They report that NPC2 mediated cholesterol transfer is stimulated greatly by BMP and a little by CER, but inhibited by PSM. The spontaneus transfer is greatly enhanced by CER, slightly enhanced by BMP, and strongly inhibited by PSM. The aim of this project is to use molecular dynamics simulation to explain these observations.

I compare three bilayer systems rich in CER, PSM or BMP to a system without any of them, that is a bilayer composed of just POPC/DPPC phospholipids and cholesterol. I measured which bilayer cholesterol prefers using free energy calculations. The sampling was improved using replica exchange. I will update this page when I have some publishable results.

References

  1. Abdul-Hammed, Misbaudeen, et al. “Role of endosomal membrane lipids and NPC2 in cholesterol transfer and membrane fusion.” Journal of lipid research 51.7 (2010): 1747-1760.