Cholesterol binding sends long distance communication signals in proteins

October 07, 2020 - by Simone Ulmer

Humans with a high cholesterol fear the "bad cholesterol", the so-called low-density lipoprotein (LDL), because it is genetic and cannot be regulated with medication. However, a healthy occurrence of LDL is important for cellular processes. LDL takes up cholesterol esters — which contain both cholesterol and fatty acid — in the blood and transports it to the cell. In the vesicular lysosomes of the cell, the ester is broken down by enzymes. The resulting free cholesterol is then transported to other parts of the cell, such as the endoplasmic reticulum and other cell membranes, where it is needed for cell processes. A cholesterol balance (homeostasis) is created in the lysosomes.

The protein NPC1, which sits in the lysosomal membrane, seems to play an important role in cholesterol transport in the cell. It has a so-called sterol-sensing domain (SSD) in the membrane and a region known as the N-terminal domain (NTD) inside the lysosome. Based on current knowledge, the SSDs should regulate the activity of NPC1 by binding cholesterol.

Serious diseases caused by disturbed cholesterol transport

It is known that a specific pathological genetic modification of the protein NPC1 causes cholesterol esters to accumulate in the lysosomes rather than break down into free cholesterol. The disease is known as Niemann Pick type C disease, and it affects the liver and spleen, ultimately leading to neurological damage. However, the exact mechanisms leading to the accumulation of cholesterol esters are not yet understood, so a research group led by Himanshu Khandelia and Daniel Wuestner, Associate Professors at the University of Southern Denmark, explored the underlying processes with simulations run on the "Piz Daint" supercomputer at CSCS. In the process of studying how membrane proteins behave in the presence and absence of free cholesterol, they made a surprising discovery.