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

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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)40996-41004
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number49
DOIs
StatePublished - Dec 9 2005

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Clathrin
LDL Receptors
Cluster Analysis
Proteins
Vesicular Transport Adaptor Proteins
Tail
Liver
Mutation
Phosphotyrosine
Autosomal Recessive Hypercholesterolemia
Fibroblasts
Endocytosis
Cell culture
Protein Binding
Machinery
Hepatocytes
Phospholipids
Cell Culture Techniques
Defects

ASJC Scopus subject areas

  • Biochemistry

Cite this

The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits. / Garuti, Rita; Jones, Christopher; Li, Wei Ping; Michaely, Peter; Herz, Joachim; Gerard, Robert D.; Cohen, Jonathan C.; Hobbs, Helen H.

In: Journal of Biological Chemistry, Vol. 280, No. 49, 09.12.2005, p. 40996-41004.

Research output: Contribution to journalArticle

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