The modular adaptor protein ARH promotes LDLR clustering into clathrin-coated pits

doi:10.1074/jbc.M509394200

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The modular adaptor protein ARH promotes LDLR clustering into clathrin-coated pits

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

Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9046

Corresponding Author: Helen.Hobbs{at}UTSouthwestern.edu

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 (PTB) 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.

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