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Papers In Press, published online ahead of print February 1, 2010
J. Lipid Res., doi:10.1194/jlr.M000422

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Journal of Lipid Research, Vol. 51, 297-308, February 2010
Copyright © 2010 by American Society for Biochemistry and Molecular Biology

Mechanism of LDL binding and release probed by structure-based mutagenesis of the LDL receptor^[S]

Sha Huang^*, Lisa Henry, Yiu Kee Ho, Henry J. Pownall^** and Gabby Rudenko^1,*,

^* Life Sciences Institute, University of Michigan, Ann Arbor, Michigan
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan
Howard Hughes Medical Institute/Department of Biochemistry, Southwestern Medical Center, University of Texas, Dallas, TX
Department of Molecular Genetics, Southwestern Medical Center, University of Texas, Dallas, TX
^** Baylor College of Medicine, Department of Medicine, Houston, TX

¹ To whom correspondence should be addressed. e-mail: rudenko{at}umich.edu

The LDL receptor (LDL-R) mediates cholesterol metabolism in humans by binding and internalizing cholesterol transported by LDL. Several different molecular mechanisms have been proposed for the binding of LDL to LDL-R at neutral plasma pH and for its release at acidic endosomal pH. The crystal structure of LDL-R at acidic pH shows that the receptor folds back on itself in a closed form, obscuring parts of the ligand binding domain with the epidermal growth factor (EGF)-precursor homology domain. We have used a structure-based site-directed mutagenesis approach to examine 12 residues in the extracellular domain of LDL-R for their effect on LDL binding and release. Our studies show that the interface between the ligand binding domain and the EGF-precursor homology domain seen at acidic pH buries residues mediating both LDL binding and release. Our results are consistent with an alternative model of LDL-R whereby multiple modules of the extracellular domain interact with LDL at neutral pH, concurrently positioning key residues so that at acidic pH the LDL-R:LDL interactions become unfavorable, triggering release. After LDL release, the closed form of LDL-R may target its return to the cell surface.

Supplementary key words cholesterol metabolism • cell surface receptor • receptor:ligand interaction

Abbreviations: apo, apolipoprotein; EGF, epidermal growth factor; FH, familial hypercholesterolemia; LDL-R, low density lipoprotein receptor; RAP, receptor-associated protein; WT, wild type

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