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      Mechanisms of Regulation of the Chemokine-Receptor Network

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          Abstract

          The interactions of chemokines with their G protein-coupled receptors promote the migration of leukocytes during normal immune function and as a key aspect of the inflammatory response to tissue injury or infection. This review summarizes the major cellular and biochemical mechanisms by which the interactions of chemokines with chemokine receptors are regulated, including: selective and competitive binding interactions; genetic polymorphisms; mRNA splice variation; variation of expression, degradation and localization; down-regulation by atypical (decoy) receptors; interactions with cell-surface glycosaminoglycans; post-translational modifications; oligomerization; alternative signaling responses; and binding to natural or pharmacological inhibitors.

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          Most cited references218

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          Chemokines: a new classification system and their role in immunity.

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            Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists.

            Chemokine receptors are critical regulators of cell migration in the context of immune surveillance, inflammation, and development. The G protein-coupled chemokine receptor CXCR4 is specifically implicated in cancer metastasis and HIV-1 infection. Here we report five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5 to 3.2 angstrom resolution. All structures reveal a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling. The location and shape of the ligand-binding sites differ from other G protein-coupled receptors and are closer to the extracellular surface. These structures provide new clues about the interactions between CXCR4 and its natural ligand CXCL12, and with the HIV-1 glycoprotein gp120.
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              Transduction of receptor signals by beta-arrestins.

              The transmission of extracellular signals to the interior of the cell is a function of plasma membrane receptors, of which the seven transmembrane receptor family is by far the largest and most versatile. Classically, these receptors stimulate heterotrimeric G proteins, which control rates of generation of diffusible second messengers and entry of ions at the plasma membrane. Recent evidence, however, indicates another previously unappreciated strategy used by the receptors to regulate intracellular signaling pathways. They direct the recruitment, activation, and scaffolding of cytoplasmic signaling complexes via two multifunctional adaptor and transducer molecules, beta-arrestins 1 and 2. This mechanism regulates aspects of cell motility, chemotaxis, apoptosis, and likely other cellular functions through a rapidly expanding list of signaling pathways.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                07 February 2017
                February 2017
                : 18
                : 2
                : 342
                Affiliations
                [1 ]Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; jenni.hayward@ 123456monash.edu (J.A.H.); cheng.huang@ 123456monash.edu (C.H.); zil.huma@ 123456monash.edu (Z.E.H.); julie.sanchez@ 123456monash.edu (J.S.)
                [2 ]Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
                Author notes
                [* ]Correspondence: martin.stone@ 123456monash.edu ; Tel.: +61-3-9902-9246
                Article
                ijms-18-00342
                10.3390/ijms18020342
                5343877
                28178200
                a0d69af4-1c14-45a8-9708-1ee6fb4566f9
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 December 2016
                : 26 January 2017
                Categories
                Review

                Molecular biology
                chemokine,chemokine receptor,regulation,binding,expression,glycosaminoglycan,post-translational modification,oligomerization,signaling,inhibitor

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