title: The DRF motif of CXCR6 as chemokine receptor adaptation to adhesion.
abstract: The CXC-chemokine receptor 6 (CXCR6) is a class A GTP-binding protein-coupled receptor (GPCRs) that mediates adhesion of leukocytes by interacting with the transmembrane cell surface-expressed chemokine ligand 16 (CXCL16), and also regulates leukocyte migration by interacting with the soluble shed variant of CXCL16. In contrast to virtually all other chemokine receptors with chemotactic activity, CXCR6 carries a DRF motif instead of the typical DRY motif as a key element in receptor activation and G protein coupling. In this work, modeling analyses revealed that the phenylalanine F3.51 in CXCR6 might have impact on intramolecular interactions including hydrogen bonds by this possibly changing receptor function. Initial investigations with embryonic kidney HEK293 cells and further studies with monocytic THP-1 cells showed that mutation of DRF into DRY does not influence ligand binding, receptor internalization, receptor recycling, and protein kinase B (AKT) signaling. Adhesion was slightly decreased in a time-dependent manner. However, CXCL16-induced calcium signaling and migration were increased. Vice versa, when the DRY motif of the related receptor CX3CR1 was mutated into DRF the migratory response towards CX3CL1 was diminished, indicating that the presence of a DRF motif generally impairs chemotaxis in chemokine receptors. Transmembrane and soluble CXCL16 play divergent roles in homeostasis, inflammation, and cancer, which can be beneficial or detrimental. Therefore, the DRF motif of CXCR6 may display a receptor adaptation allowing adhesion and cell retention by transmembrane CXCL16 but reducing the chemotactic response to soluble CXCL16. This adaptation may avoid permanent or uncontrolled recruitment of inflammatory cells as well as cancer metastasis.
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Koenen
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Aaron
authors.initials: A
authors.lastname: Babendreyer
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Schumacher
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pasqualon
authors.affiliation: Institute of Molecular and Cellular Anatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schwarz
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Seifert
authors.affiliation: Laboratory of Biomolecular Research and Condensed Matter Theory Group, Paul Scherrer Institute, Villigen, Switzerland.
authors.forename: Xavier
authors.initials: X
authors.lastname: Deupi
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Daniela
authors.identifier: http://orcid.org/0000-0002-9702-8581
authors.initials: D
authors.lastname: Dreymueller
mesh_terms: D000220:Adaptation, Biological; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D020013:Calcium Signaling; D002448:Cell Adhesion; D002460:Cell Line; D002462:Cell Membrane; D002465:Cell Movement; D002633:Chemotaxis; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C106330:CXCR6 protein, human; D008024:Ligands; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D011991:Receptors, Virus; D051057:Proto-Oncogene Proteins c-akt