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The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor.

Publication ,  Journal Article
Wu, J-H; Peppel, K; Nelson, CD; Lin, F-T; Kohout, TA; Miller, WE; Exum, ST; Freedman, NJ
Published in: J Biol Chem
November 7, 2003

Endocytosis of the low density lipoprotein (LDL) receptor (LDLR) in coated pits employs the clathrin adaptor protein ARH. Similarly, agonist-dependent endocytosis of heptahelical receptors in coated pits employs the clathrin adaptor beta-arrestin proteins. In mice fed a high fat diet, we found that homozygous deficiency of beta-arrestin2 increased total and LDL plus intermediate-density lipoprotein cholesterol levels by 23 and 53%, respectively (p < 0.05), but had no effect on high density lipoprotein cholesterol levels. We therefore tested whether beta-arrestins could affect the constitutive endocytosis of the LDLR. When overexpressed in cells, beta-arrestin1 and beta-arrestin2 each associated with the LDLR, as judged by co-immunoprecipitation, and augmented LDLR endocytosis by approximately 70%, as judged by uptake of fluorescent LDL. However, physiologic expression levels of only beta-arrestin2, and not beta-arrestin1, enhanced endogenous LDLR endocytosis (by 65%) in stably transfected beta-arrestin1/beta-arrestin2 double-knockout mouse embryonic fibroblasts (MEFs). Concordantly, when RNA interference was used to suppress expression of beta-arrestin2, but not beta-arrestin1, LDLR endocytosis was reduced. Moreover, beta-arrestin2-/- MEFs demonstrated LDLR endocytosis that was 50% less than cognate wild type MEFs. In fusion protein pull-down assays, beta-arrestin2 bound to the LDLR cytoplasmic tail stoichiometrically, and binding was abolished by mutation of LDLR Tyr807 to Ala. Mutation of LDLR cytoplasmic tail Ser833 to Asp enhanced both the affinity of LDLR fusion protein binding to beta-arrestin2, and the efficiency of LDLR endocytosis in cells expressing beta-arrestin2 physiologically. We conclude that beta-arrestin2 can bind to and enhance endocytosis of the LDLR, both in vitro and in vivo, and may thereby influence lipoprotein metabolism.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

November 7, 2003

Volume

278

Issue

45

Start / End Page

44238 / 44245

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Transfection
  • Recombinant Fusion Proteins
  • Receptors, LDL
  • Mutagenesis
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Lipoproteins
  • Kidney
 

Citation

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MLA
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Wu, J.-H., Peppel, K., Nelson, C. D., Lin, F.-T., Kohout, T. A., Miller, W. E., … Freedman, N. J. (2003). The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor. J Biol Chem, 278(45), 44238–44245. https://doi.org/10.1074/jbc.M309450200
Wu, Jiao-Hui, Karsten Peppel, Christopher D. Nelson, Fang-Tsyr Lin, Trudy A. Kohout, William E. Miller, Sabrina T. Exum, and Neil J. Freedman. “The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor.J Biol Chem 278, no. 45 (November 7, 2003): 44238–45. https://doi.org/10.1074/jbc.M309450200.
Wu J-H, Peppel K, Nelson CD, Lin F-T, Kohout TA, Miller WE, et al. The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor. J Biol Chem. 2003 Nov 7;278(45):44238–45.
Wu, Jiao-Hui, et al. “The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor.J Biol Chem, vol. 278, no. 45, Nov. 2003, pp. 44238–45. Pubmed, doi:10.1074/jbc.M309450200.
Wu J-H, Peppel K, Nelson CD, Lin F-T, Kohout TA, Miller WE, Exum ST, Freedman NJ. The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor. J Biol Chem. 2003 Nov 7;278(45):44238–44245.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

November 7, 2003

Volume

278

Issue

45

Start / End Page

44238 / 44245

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Transfection
  • Recombinant Fusion Proteins
  • Receptors, LDL
  • Mutagenesis
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Lipoproteins
  • Kidney