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Publication Detail
Identification of NSF as a beta-arrestin1-binding protein. Implications for beta2-adrenergic receptor regulation.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    McDonald PH, Cote NL, Lin FT, Premont RT, Pitcher JA, Lefkowitz RJ
  • Publication date:
  • Pagination:
    10677, 10680
  • Journal:
    J Biol Chem
  • Volume:
  • Issue:
  • Country:
  • Print ISSN:
  • Language:
  • Keywords:
    Adenosine Triphosphate, Amino Acid Sequence, Animals, Arrestins, COS Cells, Carrier Proteins, Endocytosis, Molecular Sequence Data, N-Ethylmaleimide-Sensitive Proteins, Protein Binding, Rats, Recombinant Proteins, Vesicular Transport Proteins
Previous studies have demonstrated that beta-arrestin1 serves to target G protein-coupled receptors for internalization via clathrin-coated pits and that its endocytic function is regulated by dephosphorylation at the plasma membrane. Using the yeast two-hybrid system, we have identified a novel beta-arrestin1-binding protein, NSF (N-ethylmaleimide-sensitive fusion protein), an ATPase essential for many intracellular transport reactions. We demonstrate that purified recombinant beta-arrestin1 and NSF interact in vitro and that these proteins can be coimmunoprecipitated from cells. beta-Arrestin1-NSF complex formation exhibits a conformational dependence with beta-arrestin1 preferentially interacting with the ATP bound form of NSF. In contrast to the beta-arrestin1-clathrin interaction, however, the phosphorylation state of beta-arrestin1 does not affect NSF binding. Functionally, overexpression of NSF in HEK 293 cells significantly enhances agonist-mediated beta2-adrenergic receptor (beta2-AR) internalization. Furthermore, when coexpressed with a beta-arrestin1 mutant (betaarr1S412D) that mimics a constitutively phosphorylated form of beta-arrestin1 and that acts as a dominant negative with regards to beta2-AR internalization, NSF rescues the betaarr1S412D-mediated inhibition of beta2-AR internalization. The demonstration of beta-arrestin1-NSF complex formation and the functional consequences of NSF overexpression suggest a hitherto unappreciated role for NSF in facilitating clathrin coat-mediated G protein-coupled receptor internalization.
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