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Interaction of gamma-COP with a transport motif in the D1 receptor C-terminus

Jason C Bermak1, Ming Li, Clayton Bullock

  • 1Department of Pharmacology, University of California, Irvine 92697, USA.

European Journal of Cell Biology
|March 15, 2002
PubMed

Insights

The dopamine D1 receptor's C-terminus is crucial for proper biogenesis and cell surface transport. Hydrophobic residues in this region are key for interaction with the COPI coatomer complex, ensuring correct receptor trafficking.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • G protein-coupled receptors (GPCRs) are vital cell surface proteins.
  • Defective GPCR biogenesis, often due to C-terminal truncations, leads to inherited disorders.
  • The dopamine D1 receptor (D1R) is a key GPCR involved in various neurological functions.

Purpose of the Study:

  • To investigate the structural role of the D1 receptor's C-terminus in its biogenesis and cell surface transport.
  • To identify specific C-terminal regions and residues critical for D1 receptor trafficking.
  • To elucidate the molecular mechanism underlying D1 receptor transport and identify interacting proteins.

Main Methods:

  • Generation of deletion and substitution mutants of the dopamine D1 receptor.
  • Fusion of mutant receptors to green fluorescent protein (GFP) for subcellular localization studies.
  • In vitro co-precipitation and pull-down assays to investigate protein interactions, specifically with the COPI coatomer complex.

Main Results:

  • Mutations disrupting hydrophobic residues in the proximal C-terminus caused ER retention and abolished D1 receptor function.
  • Substitutions conserving C-terminal hydrophobicity allowed normal cell surface expression and function.
  • The D1 receptor C-terminus directly associates with the gamma-subunit of the COPI coatomer complex.
  • Mutations impairing COPI binding also disrupted cell surface transport, while conservative mutations restored both.

Conclusions:

  • Hydrophobic residues in the proximal C-terminus of the D1 receptor are essential for proper receptor biogenesis and trafficking.
  • Association with the COPI coatomer complex via these hydrophobic residues plays a critical role in D1 receptor transport to the cell surface.
  • This interaction mechanism provides insight into GPCR biogenesis and potential therapeutic targets for related disorders.

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