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Molecular Pharmacology

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Research ArticleArticle

Selectivity in the Use of Gi/o Proteins Is Determined by the DRF Motif in CXCR6 and Is Cell-Type Specific

Satya P. Singh, John F. Foley, Hongwei H. Zhang, Darrell E. Hurt, Jennifer L. Richards, Craig S. Smith, Fang Liao and Joshua M. Farber
Molecular Pharmacology November 2015, 88 (5) 894-910; DOI: https://doi.org/10.1124/mol.115.099960
Satya P. Singh
Laboratory of Molecular Immunology (S.P.S., J.F.F., H.H.Z., J.L.R., C.S.S., F.L., J.M.F.) and Bioinformatics and Scientific IT Program, Office of Technology Information Systems, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (D.E.H.); and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, Maryland (C.S.S.)
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John F. Foley
Laboratory of Molecular Immunology (S.P.S., J.F.F., H.H.Z., J.L.R., C.S.S., F.L., J.M.F.) and Bioinformatics and Scientific IT Program, Office of Technology Information Systems, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (D.E.H.); and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, Maryland (C.S.S.)
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Hongwei H. Zhang
Laboratory of Molecular Immunology (S.P.S., J.F.F., H.H.Z., J.L.R., C.S.S., F.L., J.M.F.) and Bioinformatics and Scientific IT Program, Office of Technology Information Systems, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (D.E.H.); and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, Maryland (C.S.S.)
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Darrell E. Hurt
Laboratory of Molecular Immunology (S.P.S., J.F.F., H.H.Z., J.L.R., C.S.S., F.L., J.M.F.) and Bioinformatics and Scientific IT Program, Office of Technology Information Systems, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (D.E.H.); and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, Maryland (C.S.S.)
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Jennifer L. Richards
Laboratory of Molecular Immunology (S.P.S., J.F.F., H.H.Z., J.L.R., C.S.S., F.L., J.M.F.) and Bioinformatics and Scientific IT Program, Office of Technology Information Systems, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (D.E.H.); and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, Maryland (C.S.S.)
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Craig S. Smith
Laboratory of Molecular Immunology (S.P.S., J.F.F., H.H.Z., J.L.R., C.S.S., F.L., J.M.F.) and Bioinformatics and Scientific IT Program, Office of Technology Information Systems, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (D.E.H.); and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, Maryland (C.S.S.)
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Fang Liao
Laboratory of Molecular Immunology (S.P.S., J.F.F., H.H.Z., J.L.R., C.S.S., F.L., J.M.F.) and Bioinformatics and Scientific IT Program, Office of Technology Information Systems, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (D.E.H.); and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, Maryland (C.S.S.)
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Joshua M. Farber
Laboratory of Molecular Immunology (S.P.S., J.F.F., H.H.Z., J.L.R., C.S.S., F.L., J.M.F.) and Bioinformatics and Scientific IT Program, Office of Technology Information Systems, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (D.E.H.); and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, Maryland (C.S.S.)
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Abstract

CXCR6, the receptor for CXCL16, is expressed on multiple cell types and can be a coreceptor for human immunodeficiency virus 1. Except for CXCR6, all human chemokine receptors contain the D3.49R3.50Y3.51 sequence, and all but two contain A3.53 at the cytoplasmic terminus of the third transmembrane helix (H3C), a region within class A G protein–coupled receptors that contacts G proteins. In CXCR6, H3C contains D3.49R3.50F3.51I3.52V3.53 at positions 126–130. We investigated the importance and interdependence of the canonical D126 and the noncanonical F128 and V130 in CXCR6 by mutating D126 to Y, F128 to Y, and V130 to A singly and in combination. For comparison, we mutated the analogous positions D142, Y144, and A146 to Y, F, and V, respectively, in CCR6, a related receptor containing the canonical sequences. Mutants were analyzed in both human embryonic kidney 293T and Jurkat E6-1 cells. Our data show that for CXCR6 and/or CCR6, mutations in H3C can affect both receptor signaling and chemokine binding; noncanonical H3C sequences are functionally linked, with dual changes mitigating the effects of single mutations; mutations in H3C that compromise receptor activity show selective defects in the use of individual Gi/o proteins; and the effects of mutations in H3C on receptor function and selectivity in Gi/o protein use can be cell-type specific. Our findings indicate that the ability of CXCR6 to make promiscuous use of the available Gi/o proteins is exquisitely dependent on sequences within the H3C and suggest that the native sequence allows for preservation of this function across different cellular environments.

Footnotes

    • Received May 15, 2015.
    • Accepted August 21, 2015.
  • This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

  • dx.doi.org/10.1124/mol.115.099960.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 88 (5)
Molecular Pharmacology
Vol. 88, Issue 5
1 Nov 2015
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Research ArticleArticle

Roles for Noncanonical Sequences in CXCR6

Satya P. Singh, John F. Foley, Hongwei H. Zhang, Darrell E. Hurt, Jennifer L. Richards, Craig S. Smith, Fang Liao and Joshua M. Farber
Molecular Pharmacology November 1, 2015, 88 (5) 894-910; DOI: https://doi.org/10.1124/mol.115.099960

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Research ArticleArticle

Roles for Noncanonical Sequences in CXCR6

Satya P. Singh, John F. Foley, Hongwei H. Zhang, Darrell E. Hurt, Jennifer L. Richards, Craig S. Smith, Fang Liao and Joshua M. Farber
Molecular Pharmacology November 1, 2015, 88 (5) 894-910; DOI: https://doi.org/10.1124/mol.115.099960
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