Rudenko finally found the right chemical conditions to produce a baker's dozen of identical receptors and then took a "snapshot." What she and Deisenhofer saw, and published December 20, 2002 in Science, is a 3-D picture of what the researchers think the receptor looks like after releasing LDL.
At neutral pH (like the pH in blood), the LDL receptor binds LDL on the cell surface. In this state, the receptor is likely to look "long and floppy and all of the modules are aligned like a long string of beads," Rudenko says.
However, once internalized in the cell, in a compartment with acidic pH, the LDL receptor seems to snap shut, releasing LDL again. In this state, it acts something like a folding cellphone that can be snapped together to shield its buttons; the receptor similarly doubles over on itself to cover its binding domains. The receptor is then effectively closed, and the LDL is free to be taken apart elsewhere for use by the cell. The receptor recycles back to the cell surface, ready for new duty.
"You want receptors to bind tightly, but then let go of their cargo at the right moment. The system around the LDL receptor does this by decreasing pH and generating an internal competition for the ligand-binding site," Deisenhofer says. "I would expect to see this kind of action in a lot of receptors that transport molecules into the cell."
Deisenhofer's new findings relate to some of his earlier research on how statin drugs work to reduce cholesterol. As reported earlier in Science (May 11, 2001), Deisenhofer and colleagues used x-ray crystallography to show how six different statin compoundssuch as atorvastatin and simvastatininhibit the liver enzyme HMG-CoA reductase, which catalyzes a key step in cholesterol production.
The scientists are now working to understand how alterations in the amino acid sequence in critical regions of the LDL receptor might cause familial hypercholesterolemia, a common inherited disease marked by high cholesterol levels, atherosclerosis, and increased risk of a heart attack early in life.
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Photo: Reid Horn; Image: From Rudenko, G., et al. 2002. Science 298:2353-2358. © 2002 AAAS.
Reprinted from the HHMI Bulletin,
September 2003, pages 10-19.
©2003 Howard Hughes Medical Institute