Structural Analysis Explains LDL Receptor Function

A study has revealed new information about the structure of the low-density lipoprotein (LDL) receptor and suggested a mechanism by which the receptor transfers LDL into the interior of the cell. The study was published November 29, 2002, in the online edition of Science.

Previous work had shown that LDL receptors bind LDL on the cell surface under conditions of neutral pH. A process known as receptor-mediated endocytosis moves the receptor-LDL complex into the acidic environment of the endosomes. The LDL is released at pH 6 or lower, and the receptor returns to the outer surface of the plasma membrane to repeat the process.

The LDL receptor's extracellular domain consists of two major parts, the LDL binding region and the ‘beta-propeller' region. In the current study, researchers from the University of Texas Southwestern Medical Center (Dallas, USA) studied the structure of the LDL receptor under acidic conditions. They found that the LDL binding region attached to the ‘beta-propeller' region at low pH and thus could not bind to LDL. The ‘beta-propeller' acted as an alternate substrate for the ligand-binding domain, binding in a calcium dependent way and promoting lipoprotein release.

"This research will help scientists understand the mechanics of how our bodies absorb cholesterol from the blood,” explained senior author Dr. Jophann Deisenhofer, professor of biochemistry at UT Southwestern. "Hopefully, we can use the information to develop treatments for people with mutations that diminish the functions of their LDL receptors.”



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Univ. of Texas Southwestern Medical Center