title: Function, diversity and therapeutic potential of the N-terminal domain of human chemokine receptors.
abstract: Chemokines and their receptors play fundamental roles in many physiological and pathological processes such as leukocyte trafficking, inflammation, cancer and HIV-1 infection. Chemokine-receptor interactions are particularly intricate and therefore require precise orchestration. The flexible N-terminal domain of human chemokine receptors has regularly been demonstrated to hold a crucial role in the initial recognition and selective binding of the receptor ligands. The length and the amino acid sequences of the N-termini vary considerably among different receptors but they all show a high content of negatively charged residues and are subject to post-translational modifications such as O-sulfation and N- or O-glycosylation. In addition, a conserved cysteine that is most likely engaged in a receptor-stabilizing disulfide bond delimits two functionally distinct parts in the N-terminus, characterized by specific molecular signatures. Structural analyses have shown that the N-terminus of chemokine receptors recognizes a groove on the chemokine surface and that this interaction is stabilized by high-affinity binding to a conserved sulfotyrosine-binding pocket. Altogether, these data provide new insights on the chemokine-receptor molecular interplay and identify the receptor N-terminus-binding site as a new target for the development of therapeutic molecules. This review presents and discusses the diversity and function of human chemokine receptor N-terminal domains and provides a comprehensive annotated inventory of their sequences, laying special emphasis on the presence of post-translational modifications and functional features. Finally, it identifies new molecular signatures and proposes a computational model for the positioning and the conformation of the CXCR4 N-terminus grafted on the first chemokine receptor X-ray structure.
authors.affiliation: Laboratory of Retrovirology, Public Research Center for Health, Luxembourg, Luxembourg. martyna.szpakowska@crp-sante.lu
authors.forename: Martyna
authors.initials: M
authors.lastname: Szpakowska
authors.forename: Virginie
authors.initials: V
authors.lastname: Fievez
authors.forename: Karthik
authors.initials: K
authors.lastname: Arumugan
authors.forename: Nico
authors.initials: N
authors.lastname: van Nuland
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Schmit
authors.forename: Andy
authors.initials: A
authors.lastname: Chevigné
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018925:Chemokines / Q000737:chemistry / Q000378:metabolism; D006031:Glycosylation; D015497:HIV-1 / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D008969:Molecular Sequence Data; D010961:Plasmodium / Q000502:physiology; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D015728:Receptors, HIV / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D018925:Chemokines; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D015728:Receptors, HIV