The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits

J Biol Chem. 2005 Dec 9;280(49):40996-1004. doi: 10.1074/jbc.M509394200. Epub 2005 Sep 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 2 / metabolism
  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Binding Sites
  • Cell Fusion
  • Cell Line, Transformed
  • Cell Membrane / chemistry
  • Clathrin / metabolism
  • Clathrin-Coated Vesicles / metabolism*
  • Cytoplasm / chemistry
  • Fibroblasts
  • Fluorescent Antibody Technique
  • Gene Expression
  • Hepatocytes
  • Humans
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Microscopy, Immunoelectron
  • Mutation
  • Rats
  • Receptors, LDL / chemistry
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Recombinant Proteins / analysis
  • Structure-Activity Relationship
  • Transfection


  • Adaptor Protein Complex 2
  • Adaptor Proteins, Signal Transducing
  • Clathrin
  • LDLRAP1 protein, human
  • Ldlrap1 protein, mouse
  • Receptors, LDL
  • Recombinant Proteins