Functional dissection of an AP-2 β2 appendage-binding sequence within the autosomal recessive hypercholesterolemia protein

Sanjay K Mishra, Peter Keyel, Melissa Edeling, Amie Dupin, David J Owen, Linton M Traub

Research output: Contribution to journalArticle

Abstract

The autosomal recessive hypercholesterolemia (ARH) protein plays a critical role in regulating plasma low density lipoprotein (LDL) levels. Inherited defects in ARH lead to a hypercholesterolemia that closely phenocopies that caused by a defective LDL receptor. The elevated serum LDL-cholesterol levels typical of ARH patients and the pronounced accumulation of the LDL receptor at the cell surface of hepatocytes in ARH-null mice argue that ARH operates by promoting the internalization of the LDL receptor within clathrin-coated vesicles. ARH contains an amino-terminal phosphotyrosine-binding domain that associates physically with the LDL receptor internalization sequence and with phosphoinositides. The carbosyl-terminal half of ARH contains a clathrin-binding sequence and a separate AP-2 adaptor binding region providing a plausible mechanism for how ARH can act as an endocytic adaptor or CLASP (clathrin-associated sorting protein) to couple LDL receptors with the clathrin machinery. Bec
Original languageEnglish
Pages (from-to)19270-19280
JournalJournal of Biological Chemistry
StatePublished - 2005

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