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J. Biol. Chem., Vol. 279, Issue 32, 34023-34031, August 6, 2004

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The Modular Adaptor Protein ARH Is Required for Low Density Lipoprotein (LDL) Binding and Internalization but Not for LDL Receptor Clustering in Coated Pits^*

Peter Michaely, Wei-Ping Li, Richard G. W. Anderson, Jonathan C. Cohen¶||**, and Helen H. Hobbs¶||¶¶

From the Departments of Cell Biology, ^¶Internal Medicine, and Molecular Genetics, the ^||McDermott Center for Human Growth and Development, the ^**Center for Human Nutrition, and the Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390

ARH is an adaptor protein required for efficient endocytosis of low density lipoprotein (LDL) receptors (LDLRs) in selected tissues. Individuals lacking ARH (ARH^-/-) have severe hypercholesterolemia due to impaired hepatic clearance of LDL. Immortalized lymphocytes, but not fibroblasts, from ARH-deficient subjects fail to internalize LDL. To further define the role of ARH in LDLR function, we compared the subcellular distribution of the LDLR in lymphocytes from normal and ARH^-/- subjects. In normal lymphocytes LDLRs were predominantly located in intracellular compartments, whereas in ARH^-/- cells the receptors were almost exclusively on the plasma membrane. Biochemical assays and quantification of LDLR by electron microscopy indicated that ARH^-/- lymphocytes had >20-fold more LDLR on the cell surface and a 27-fold excess of LDLR outside of coated pits. The accumulation of LDLR on the cell surface was not due to failure of receptors to localize in coated pits since the number of LDLRs in coated pits was similar in ARH^-/- and normal cells. Despite the dramatic increase in cell surface receptors, LDL binding was only 2-fold higher in the ARH^-/- lymphocytes. These findings indicate that ARH is required not only for internalization of the LDL·LDLR complex but also for efficient binding of LDL to the receptor and suggest that ARH stabilizes the associations of the receptor with LDL and with the invaginating portion of the budding pit, thereby increasing the efficiency of LDL internalization.

Received for publication, May 11, 2004 , and in revised form, May 26, 2004.

^* This work was supported in part by National Institutes of Health Grant HL-20948 and the Donald W. Reynolds Foundation. 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.

Supported in part by the Cecil H. Green Distinguished Chair in Cellular and Molecular Biology.

^¶¶ To whom correspondence should be addressed: Dept. of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75290-9046. Tel.: 214-648-6724; Fax: 214-648-7539; E-mail: Helen.Hobbs{at}utsouthwestern.edu.

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