Proteins that transport cholesterol identified

Structural data reveals key aspects of function

The structure of the lipid transfer protein StarD4 reveals an inner "hydrophobic" tunnel – the perfect hiding place for a water-fearing cholesterol molecule.

Professor Jan Breslow and colleagues, including biomedical fellow Raymond Soccio, recently discovered a novel subfamily of the START domain lipid transfer proteins, which are thought to shuttle lipids such as cholesterol within cells.

In addition, former Professor Stephen Burley and postdoc Michael Romanowski have solved the structure of one of these important proteins, revealing key aspects of its function.

The recent findings were reported in two papers in the Proceedings of the National Academy of Sciences.

Although cholesterol is an essential component of cell membranes and the precursor of steroid hormones, bile acids and vitamin D, too much of it can contribute to heart disease and stroke. The body must therefore tightly regulate blood levels of this important molecule.

But, like oil and water, fatty or “hydrophobic” cholesterol molecules don’t mix with the watery insides of a cell. Consequently, specialized transport proteins such as the START proteins are needed to carry these and other related molecules through the cell.

To identify novel cholesterol-regulated genes, Soccio and Breslow used cDNA microarrays. They fed mice a diet high in cholesterol and observed that levels of one gene – later named StarD4 because of its similarity to known START proteins – dropped almost three-fold in the liver. Scanning DNA databases, they found two other related genes, StarD5 and StarD6.

Romanowski and Burley then used X-ray crystallography to solve the structure of StarD4, which revealed a hydrophobic tunnel at its core—the perfect hiding place for a water-fearing cholesterol molecule.

Further studies investigating the precise physiological function of these three proteins are underway in the Breslow laboratory.