|Title||Function, diversity and therapeutic potential of the N-terminal domain of human chemokine receptors.|
|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Szpakowska, M., V. Fievez, K. Arumugan, N. A. J. van Nuland, J-C. Schmit, and A. Chevigné|
|Date Published||2012 Nov 15|
|Keywords||Amino Acid Sequence, Animals, Antibodies, Monoclonal, Chemokines, Glycosylation, Herpesvirus 8, Human, HIV-1, Host-Pathogen Interactions, Humans, Molecular Sequence Data, Plasmodium, Protein Conformation, Protein Processing, Post-Translational, Receptors, Chemokine, Receptors, CXCR4, Receptors, HIV|
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.
|Alternate Journal||Biochem. Pharmacol.|