Changes in pH cause the protein to open and close in different environments.
A close look at one protein shows how it shuttles molecular passengers into cells in the kidney, brain and elsewhere.
The LRP2 protein is part of the delivery service, picking up certain molecules outside the cell and ferrying them inside. Now, three-dimensional maps of LRP2 reveal the structure of the protein and how it captures and releases molecules, researchers report Feb. 6 in Cell . The protein takes a more open form, like a net, at near-neutral pH outside the cells. But in the acidic environment inside the cell, the protein contorts to disembark the passengers.
The shape of the LRP2 structure—and how it provides so many functions—has puzzled scientists for decades. The protein helps the kidneys and brain filter out toxic substances, and it also works in other places, such as the lungs and inner ears. When the protein doesn’t function properly, a host of diseases 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 stem from the protein’s multiple responsibilities—it binds to more than 75 different molecules. That’s a huge amount for one protein, which is why it’s called “molecular Velcro,” says nephrologist Jonathan Barash of Columbia University.
Normally, LRP2 sits on the surface of the cell membrane, waiting to engage a passing molecule. After the protein binds to the molecule, the cell engulfs the portion of its surface that contains the protein, forming an internal vesicle called an endosome. LRP2 then releases the molecule into the cell, and the endosome returns the protein to the surface.
To understand this shuttle system, Barash and colleagues collected LRP2 from 500 mouse kidneys. The researchers placed part of the protein in a solution with an extracellular pH of 7.5, and part of it in a solution that mimics endosomes, with a pH of 5.2. Using a cryo-electron microscope, they imaged the proteins and then stitched the images together in a computer, creating three-dimensional maps of the protein in both open and closed structures.
This three-dimensional model of the LRP2 protein shows how it changes from a more open structure at near-neutral pH outside the cell to a crumpled form at acidic pH inside the cell. These pH-driven conformational changes allow LRP2 to capture molecules outside the cell and release them inside. Two copies of the same protein—one pink and one blue—make up LRP2.
The researchers suggest that the charged calcium atoms keep the protein open at the extracellular pH. But when the pH drops due to hydrogen ions entering the endosome, the hydrogen ions displace the calcium ions, causing the protein to contract.
