3-D maps of protein show how it helps the body filter out toxic substances

A closer look at one protein shows how it moves molecular passengers into cells in the kidneys, brain and elsewhere.

The protein LRP2 is part of the delivery service, taking certain molecules out of the cell and bringing them into the cells. Now, 3-D mapping reveals the structure of the LRP2 protein and how it captures and releases molecules, researchers report February 6 in Cell. Proteins use a more open shape, like a net, at a near-neutral pH outside the cells. However, in the acidic environment inside the cells, proteins are secreted as if there were no protein.

Figuring out the structure of LRP2 – and how it can perform so many functions – has puzzled scientists for decades. Protein helps the kidneys and brain filter out toxic substances, and it works in other areas as well, such as the lungs and inner ears. When protein doesn’t function properly, many health conditions can occur, including chronic kidney disease and Donnais-Barrow syndrome, a genetic disorder that affects the kidneys and brain.

The various conditions associated with LRP2 dysfunction come from the protein’s many functions – it binds to more than 75 different molecules. It’s an enormous amount of one protein, earning it the nickname “the molecular flypaper,” says nephrologist Jonathan Barasch of Columbia University.

Typically, LRP2 sits at the surface of the cell membrane, waiting for a passing molecule to snag it. After the protein binds to the molecule, the cell wraps around part of its surface containing the protein, forming an internal endosome bubble. LRP2 then releases the molecule inside the cell and carries the protein to the surface of the endosome.

To understand this shuttle system, Barasch and colleagues collected LRP2 from 500 mouse kidneys. Researchers put some proteins in solution at an extracellular pH of 7.5, partially in an endosome-micing solution of pH 5.2. Using a cryo-electron microscope, they capture images of the protein and record the images on a computer, rendering 3-D maps of the protein in both open and closed formations.

The researchers suggest that the charged calcium atoms keep the protein open at the extracellular pH. But as the pH drops due to hydrogen ions flowing into the endosome, the hydrogen ions deposit calcium ions, causing the protein to contract.