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Combining Mass Spectrometry and Pull-Down Techniques for the Study of Receptor Heteromerization. Direct Epitope−Epitope Electrostatic Interactions between Adenosine A2A and Dopamine D2 Receptors

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Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, E-08028, Spain, National Institute on Drug Abuse, Intramural Research Program, NIH, Department of Health and Human Services, Baltimore, Maryland 21224, Max-Delbrück-Center for Molecular Medicine, D-13092 Berlin-Buch, Germany, Department of Neuroscience, Division of Cellular and Molecular Neurochemistry, Karolinska Institutet, S-171 77 Stockholm, Sweden, and Section of Physiology, Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy
Cite this: Anal. Chem. 2004, 76, 18, 5354–5363
Publication Date (Web):August 3, 2004
Copyright © 2004 American Chemical Society

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    Previous results from FRET and BRET experiments and computational analysis (docking simulations) have suggested that a portion of the third intracellular loop (I3) of the human dopamine D2 receptor (D2R) and the C-tail from the human adenosine A2A receptor (A2AR) are involved in A2AR−D2R heteromerization. The results of the present studies, using pull-down and mass spectrometry experiments, suggest that A2AR−D2R heteromerization depends on an electrostatic interaction between an Arg-rich epitope from the I3 of the D2R (217RRRRKR222) and two adjacent Asp residues (DD401-402) or a phosphorylated Ser (S374) residue in the C-tail of the A2AR. A GST-fusion protein containing the C-terminal domain of the A2AR (GST-A2ACT) was able to pull down the whole D2R solubilized from D2R-tranfected HEK-293 cells. Second, a peptide corresponding to the Arg-rich I3 region of the D2R (215VLRRRRKRVN224) and bound to Sepharose was able to pull down both GST-A2ACT and the whole A2AR solubilized from A2AR-tranfected HEK-293 cells. Finally, mass spectometry and pull-down data showed that the Arg-rich D2R epitope binds to two different epitopes from the C-terminal part of the A2AR, containing the two adjacent Asp residues or the phosphorylated Ser residue (388HELKGVCPEPPGLDDPLAQDGAVGS412 and 370SAQEpSQGNT378). The present results are the first example of epitope−epitope electrostatic interaction underlying receptor heteromerization, a new, expanding area of protein−protein interactions.

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     University of Barcelona.

     NIH, Department of Health and Human Services.


     Max-Delbrück-Center for Molecular Medicine.

     Karolinska Institutet.

     University of Modena.


     To whom correspondence should be addressed. Tel.:  410-550-1507. E-mail:  [email protected].

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