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Identification of amino acid residues crucial for chemokine receptor dimerization

Nature Immunologyvolume 5pages216223 (2004) | Download Citation

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Abstract

Chemokines coordinate leukocyte trafficking by promoting oligomerization and signaling by G protein–coupled receptors; however, it is not known which amino acid residues of the receptors participate in this process. Bioinformatic analysis predicted that Ile52 in transmembrane region-1 (TM1) and Val150 in TM4 of the chemokine receptor CCR5 are key residues in the interaction surface between CCR5 molecules. Mutation of these residues generated nonfunctional receptors that could not dimerize or trigger signaling. In vitro and in vivo studies in human cell lines and primary T cells showed that synthetic peptides containing these residues blocked responses induced by the CCR5 ligand CCL5. Fluorescence resonance energy transfer showed the presence of preformed, ligand-stabilized chemokine receptor oligomers. This is the first description of the residues involved in chemokine receptor dimerization, and indicates a potential target for the modification of chemokine responses.

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Acknowledgements

We thank J.P. Albar for peptide synthesis, J. Gutiérrez for chemokine receptor transfectants, M.C. Moreno-Ortíz for help with FACS analysis, and C. Bastos and C. Mark for secretarial and editorial assistance, respectively. Partially supported by grants from the Spanish Comisión Interministerial de Ciencia y Technología and from the Ministry of Health. The Department of Immunology and Oncology was founded and is supported by the Spanish Council for Scientific Research (CSIC) and by Pfizer.

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Author notes

  1. José Miguel Rodríguez-Frade and Antonio Serrano: These authors contributed equally to this work.

Affiliations

  1. Department of Immunology and Oncology, National Center of Biotechnology, Campus Universitario de Cantoblanco, Madrid, E-28049, Spain

    • Patricia Hernanz-Falcón
    • , José Miguel Rodríguez-Frade
    • , Antonio Serrano
    • , Silvia F Soriano
    • , Fernando Roncal
    • , Lucio Gómez
    • , Carlos Martínez-A
    •  & Mario Mellado
  2. Protein Design Group, National Center of Biotechnology, Campus Universitario de Cantoblanco, Madrid, E-28049, Spain

    • David Juan
    • , Antonio del Sol
    •  & Alfonso Valencia

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Correspondence to Carlos Martínez-A.

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https://doi.org/10.1038/ni1027

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