期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 280, 期 19, 页码 19270-19280出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M501029200
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资金
- NIDDK NIH HHS [R01 DK53249, 5T32 DK061296-02] Funding Source: Medline
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 beta 2 subunit, we have characterized the ARH beta 2 appendage-binding sequence in detail. Unlike the known alpha appendage-binding motifs, ARH requires an extensive sequence tract to bind the beta appendage with comparably high affinity. A minimal 16-residue sequence functions autonomously and depends upon ARH residues Asp(253), Phe(259), Leu(262), and Arg(266). We suggested that biased beta subunit engagement by ARH and the only other beta 2 appendage selective adaptor, beta-arrestin, promotes efficient incorporation of this mechanistically distinct subset of CLASPs into clathrin-coated buds.
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