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 carboxyl-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. Because the interaction with AP-2 is highly selective for the independently folded appendage domain of the β2 subunit, we have characterized the ARH β2 appendage-binding sequence in detail. Unlike the known α appendage-binding motifs, ARH requires an extensive sequence tract to bind the β appendage with comparably high affinity. A minimal 16-residue sequence functions autonomously and depends upon ARH residues Asp253, Phe259, Leu262, and Arg266. We suggested that biased β subunit engagement by ARH and the only other β2 appendage selective adaptor, β-arrestin, promotes efficient incorporation of this mechanistically distinct subset of CLASPs into clathrin-coated buds. 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 carboxyl-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. Because the interaction with AP-2 is highly selective for the independently folded appendage domain of the β2 subunit, we have characterized the ARH β2 appendage-binding sequence in detail. Unlike the known α appendage-binding motifs, ARH requires an extensive sequence tract to bind the β appendage with comparably high affinity. A minimal 16-residue sequence functions autonomously and depends upon ARH residues Asp253, Phe259, Leu262, and Arg266. We suggested that biased β subunit engagement by ARH and the only other β2 appendage selective adaptor, β-arrestin, promotes efficient incorporation of this mechanistically distinct subset of CLASPs into clathrin-coated buds. Clathrin-coated vesicles are short lived transport intermediates fabricated solely for the preferential sorting and intracellular trafficking of select transmembrane proteins, bound ligands, and lipids (1Bonifacino J.S. Lippincott-Schwartz J. Nat. Rev. Mol. Cell Biol. 2003; 4: 409-414Crossref PubMed Scopus (306) Google Scholar, 2Conner S.D. Schmid S.L. Nature. 2003; 422: 37-44Crossref PubMed Scopus (2979) Google Scholar, 3Robinson M.S. Trends Cell Biol. 2004; 14: 167-174Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar). Clathrin coats assemble at several discrete intracellular sites where, typically, different cargo molecules are sorted. As the two major clathrin-associated heterotetrameric adaptor proteins (AP-1 and AP-2) are generally restricted to particular sorting stations within the cell, a long standing model has been that adaptors direct the process of cargo selection (4Kirchhausen T. Nat. Rev. Mol. Cell Biol. 2000; 1: 187-198Crossref PubMed Scopus (416) Google Scholar). Different subunits of the adaptor complex directly engage different classes of sorting sequences. The μ2 subunit binds to YXXØ-type (where Ø is a bulky hydrophobic amino acid) sorting signals in a phosphorylation-dependent manner (3Robinson M.S. Trends Cell Biol. 2004; 14: 167-174Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar, 5Conner S.D. Schmid S.L. J. Cell Biol. 2002; 156: 921-929Crossref PubMed Scopus (222) Google Scholar, 6Bonifacino J.S. Traub L.M. Annu. Rev. Biochem. 2003; 72: 395-447Crossref PubMed Scopus (1620) Google Scholar). In the basal state, the orientation of the μ2 subunit within AP-2 makes the YXXØ interaction surface inaccessible. Phosphorylation on μ2 residue Thr156 is believed to alter the conformation of μ2 to allow productive engagement of the YXXØ sequence (7Olusanya O. Andrews P.D. Swedlow J.R. Smythe E. Curr. Biol. 2001; 11: 896-900Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 8Ricotta D. Conner S.D. Schmid S.L. von Figura K. Honing S. J. Cell Biol. 2002; 156: 791-795Crossref PubMed Scopus (202) Google Scholar, 9Collins B.M. McCoy A.J. Kent H.M. Evans P.R. Owen D.J. Cell. 2002; 109: 523-535Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar). Another sorting sequence termed the (DE)XXXL(LI) motif is recognized by AP-1, AP-2, and AP-3 (6Bonifacino J.S. Traub L.M. Annu. Rev. Biochem. 2003; 72: 395-447Crossref PubMed Scopus (1620) Google Scholar). Recent evidence suggests that the (DE)XXXL(LI) sequence is bound by a hemicomplex of the γ and σ1 subunits in AP-1 or the δ and σ3 subunits in AP-3 (10Janvier K. Kato Y. Boehm M. Rose J.R. Martina J.A. Kim B.Y. Venkatesan S. Bonifacino J.S. J. Cell Biol. 2003; 163: 1281-1290Crossref PubMed Scopus (182) Google Scholar), although the precise location of the interaction site remains to be determined. Not all cargo molecules sorted into clathrin-coated vesicles appear to utilize heterotetrameric adaptors directly, because not all sorting sequences conform to the YXXØ or (DE)XXX L(LI) types. At the plasma membrane, there are several other internalization signals/tags known (6Bonifacino J.S. Traub L.M. Annu. Rev. Biochem. 2003; 72: 395-447Crossref PubMed Scopus (1620) Google Scholar), and the growing consensus is that alternate adaptor proteins govern the endocytosis of proteins with these signals (3Robinson M.S. 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Y. B.M. Evans P.R. J. 2000; PubMed Google Scholar). is with the pronounced that a or has on the binding of ARH to the β2 appendage in We have been to the of the at the of ARH Y. J. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google of this in ARH AP-2 binding not and this is not in the ARH is that the ARH carboxyl-terminal can all of the β2 appendage binding in for the of the ARH interaction motif with the in proteins that bind to the of the AP-2 α and Traub L.M. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). these proteins, ARH not bind to the α appendage Traub L.M. S. 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