Conducted on cell lines in the lab

The finding—conducted on cell lines in the lab—has implications for how we may develop future drugs for heart disease, a rare genetic disorder affecting children and even the Ebola virus.

In a paper published recently in Cell, a team of researchers including molecular biologists from UNSW Sydney made a detailed analysis of the form and function of proteins encoded by two genes in humans—NPC1 and NPC2—and analyzed their role in transporting low-density lipoprotein (LDL) cholesterol into our body cells via lysosomes.

UNSW Science’s Professor Rob Yang says the international team of researchers, which involved scientists from Princeton University (New Jersey) and Tsinghua University (Beijing), used cryo-electron microscopes to observe proteins at the near-atomic level in great detail—something that was not possible just 10 years ago.

“Before 2013 we often had to theorize about how membrane proteins worked and how they functioned, but now we can actually see them, and seeing is believing. We were able to look at the NPC1 and NPC2 proteins and see exactly the role they play in transporting this LDL cholesterol into the cell,” Prof Yang says.

“If you imagine NPC2 bringing the cholesterol to the gate at the edge of the lysosome membrane, the NPC1 protein provides a tunnel for this cholesterol into the cell itself. Cholesterol is an important building block for our cells, but too much of it in the blood can clog our arteries leading to heart disease. Now that we understand how it gets into the cell, we can work towards developing drugs that target the NPC1 and NPC2 proteins to facilitate its influx into cells so as to lower the amount of it in the blood.”

A very serious and often fatal health problem associated with the NPC1 and -2 genes is the Niemann-Pick disease type C, often detected in young children. Mutations in the NPC1 gene can prevent LDL cholesterol from binding to the protein, leaving it trapped in the cell’s lysosomes. Over time, it builds up in cells causing cell dysfunction, and later, cell death. People with this condition experience symptoms related to progressive loss of function of nerves, the brain and other organs.