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Key Vitamin Finds Its Lock

25 January 2007 (All day)
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Hui Sun

Special delivery.
Retinol binding protein delivers vitamin A (red) to the Vitamin A receptor, also known as STRA6, which relays vitamin A into the cell.

Vitamin A is no ordinary dietary supplement. Without it, the body's immune system deteriorates, fetuses develop birth defects, and adults go blind. Now, researchers have identified the molecular lock that enables vitamin A to enter cells. The findings solve a longstanding mystery about vitamin A metabolism and could help scientists develop new ways to fight vitamin-A deficiency in the developing world.

Vitamin A, also known as retinol, is made in the liver. From there, it's carried through the blood and delivered to tissues by a molecule called retinol-binding protein (RBP). Just how vitamin A gets into cells, however, has remained a mystery. Several teams of biochemists have tried, over 3 decades, to isolate a receptor--or lock--for RBP's key. Because they always came up empty, some researchers argued that a receptor did not exist. Biochemist Hui Sun of the University of California, Los Angeles, was convinced it was out there.

Most molecular keys fit tightly into their locks; so biochemists can often use the key to fish the receptor's lock out of a solution. But based on previous evidence, Sun suspected that RBP maintained only loose contact with its receptor. To improve the chances of pulling them out together, Sun's team added a chemical called a crosslinker to 400 ground-up cow eyeballs. Crosslinkers help proteins stick together, and cow eyeballs are chock full of Vitamin A (and therefore, theoretically, the RBP receptor).

The strategy worked. When the team pulled RBP from the mix, it was attached to another protein, which resembled a receptor. To make sure they had the right receptor, called STRA6, the researchers injected its gene into cultured cells. Injected cells took up 15 times as much Vitamin A as cells without the added receptor gene, the team reports online today in Science. What's more, when the researchers used genetic tricks to reduce the amount of RBP receptor--or to make mutant receptors--the cells took up less vitamin A. And when they measured receptor levels throughout the body, the receptor was most concentrated in tissues such as the retina, brain, and spleen that gobble up vitamin A.

"The depth of this study is such that I don't think there will be a controversy anymore" about the existence of the receptor, says nutritional biochemist Sherry Tanumihardjo of the University of Wisconsin, Madison. Scientists can now find out how the receptor is regulated, she says, which could help them develop new ways to deliver vitamin A to tissues in people who don't get enough of it.

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