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J. Biol. Chem., Vol. 280, Issue 49, 40996-41004, December 9, 2005

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The Modular Adaptor Protein Autosomal Recessive Hypercholesterolemia (ARH) Promotes Low Density Lipoprotein Receptor Clustering into Clathrin-coated Pits^*

Rita Garuti1, Christopher Jones, Wei-Ping Li, Peter Michaely, Joachim Herz, Robert D. Gerard¶, Jonathan C. Cohen¶, and Helen H. Hobbs||2

From the Departments of Molecular Genetics, Cell Biology, and ^¶Internal Medicine and the ^||Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8591

Autosomal recessive hypercholesterolemia is characterized by a cell type-specific defect in low density lipoprotein receptor (LDLR) endocytosis. LDLR-mediated uptake of LDL is impaired in the liver, but not in fibroblasts of subjects with this disorder. The disease is caused by mutations in ARH, which encodes a putative adaptor protein that interacts with the cytoplasmic tail of the LDLR, phospholipids, and two components of the clathrin endocytic machinery, clathrin and adaptor protein-2 (AP-2) in vitro. To determine the physiological relevance of these interactions, we examined the effect of mutations in the ARH on LDLR location and function in polarized hepatocytes (WIF-B). The integrity of the FDNPVY sequence in the LDLR cytoplasmic tail was required for ARH-associated LDLR clustering into clathrin-coated pits. The phosphotyrosine binding domain of ARH plus either the clathrin box or the AP-2 binding region were required for both clustering and internalization of the LDLR. Parallel studies performed in vivo with the same recombinant forms of ARH in livers of Arh^-/- mice confirmed the relevance of the cell culture findings. These results demonstrate that ARH must bind the LDLR tail and either clathrin or AP-2 to promote receptor clustering and internalization of LDL.

Received for publication, August 25, 2005 , and in revised form, September 20, 2005.

^* This work was supported by National Institutes of Health Grant HL20948, the Donald W. Reynolds Foundation, and the Perot Family Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a fellowship from the International Atherosclerosis Society.

² To whom correspondence should be addressed: Dept. of Molecular Genetics, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8591. Tel.: 214-648-6724; Fax: 214-648-7539; E-mail: Helen.hobbs{at}utsouthwestern.edu.

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