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Regulation of Chemokine-Receptor Interactions and Functions
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Regulation of Chemokine-Receptor Interactions and Functions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2017) | Viewed by 83985

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Martin J. Stone

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia
Interests: chemokines; chemokine receptors; tyrosine sulfation; GPCR signaling; protein structure-function relationships

Special Issue Information

Dear Colleagues,

A hallmark feature of inflammation is the accumulation of leukocytes, which can serve to remove pathogens and necrotic tissue, but may also damage healthy tissue and exacerbate the inflammatory response. Our understanding of leukocyte recruitment in inflammation was revolutionized in the late 1980s by the discovery of chemokines (chemotactic cytokines), a family of small, secreted proteins that induce migration of selective subsets of leukocytes. Shortly afterwards, chemokines were found to exert their functions through the now familiar chemokine receptors, members of the G protein-coupled receptor (GPCR) superfamily. As their physiological and pathological functions were elucidated, chemokine receptors have become popular targets for drug development in inflammatory diseases, as well as cancer metastasis and HIV infection. Extensive research has revealed that the functions of chemokines and their receptors are regulated at numerous levels, including: genetic mutations/polymorphisms; control of expression levels; ligand internalization via functional or decoy receptors; intrinsic selectivity of chemokine-receptor binding; hetero- or homo-oligomerization of chemokines or of receptors; alternative signaling pathways; interaction of chemokines with glycosaminoglycans (GAGs); post-translational modifications; and binding to pathogen-derived inhibitors. This Special Issue of IJMS focuses on the natural and pharmacological mechanisms by which the activities of chemokines and their receptors can be regulated.

Assoc. Prof. Dr. Martin J. Stone
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Chemokine
  • Chemokine receptor
  • Regulation
  • Polymorphism
  • Decoy receptor
  • Oligomer
  • Signaling pathway
  • GAG
  • Post-translational modification
  • Inhibition

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Published Papers (13 papers)

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Editorial

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161 KiB  
Editorial
Regulation of Chemokine–Receptor Interactions and Functions
by Martin J. Stone
Int. J. Mol. Sci. 2017, 18(11), 2415; https://doi.org/10.3390/ijms18112415 - 14 Nov 2017
Cited by 15 | Viewed by 2784
Abstract
Inflammation is the body’s response to injury or infection. As early as 2000 years ago, the Roman encyclopaedist Aulus Cornelius Celsus recognised four cardinal signs of this response—redness, heat, swelling and pain; a fifth sign is loss of function.[...] Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)

Research

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3929 KiB  
Article
Differences in Sulfotyrosine Binding amongst CXCR1 and CXCR2 Chemokine Ligands
by Natasha A. Moussouras, Anthony E. Getschman, Emily R. Lackner, Christopher T. Veldkamp, Michael B. Dwinell and Brian F. Volkman
Int. J. Mol. Sci. 2017, 18(9), 1894; https://doi.org/10.3390/ijms18091894 - 03 Sep 2017
Cited by 12 | Viewed by 4673
Abstract
Tyrosine sulfation, a post-translational modification found on many chemokine receptors, typically increases receptor affinity for the chemokine ligand. A previous bioinformatics analysis suggested that a sulfotyrosine (sY)-binding site on the surface of the chemokine CXCL12 may be conserved throughout the chemokine family. However, [...] Read more.
Tyrosine sulfation, a post-translational modification found on many chemokine receptors, typically increases receptor affinity for the chemokine ligand. A previous bioinformatics analysis suggested that a sulfotyrosine (sY)-binding site on the surface of the chemokine CXCL12 may be conserved throughout the chemokine family. However, the extent to which receptor tyrosine sulfation contributes to chemokine binding has been examined in only a few instances. Computational solvent mapping correctly identified the conserved sulfotyrosine-binding sites on CXCL12 and CCL21 detected by nuclear magnetic resonance (NMR) spectroscopy, demonstrating its utility for hot spot analysis in the chemokine family. In this study, we analyzed five chemokines that bind to CXCR2, a subset of which also bind to CXCR1, to identify hot spots that could participate in receptor binding. A cleft containing the predicted sulfotyrosine-binding pocket was identified as a principal hot spot for ligand binding on the structures of CXCL1, CXCL2, CXCL7, and CXCL8, but not CXCL5. Sulfotyrosine titrations monitored via NMR spectroscopy showed specific binding to CXCL8, but not to CXCL5, which is consistent with the predictions from the computational solvent mapping. The lack of CXCL5–sulfotyrosine interaction and the presence of CXCL8–sulfotyrosine binding suggests a role for receptor post-translational modifications regulating ligand selectivity. Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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2637 KiB  
Article
CCR7 Sulfotyrosine Enhances CCL21 Binding
by Andrew J. Phillips, Deni Taleski, Chad A. Koplinski, Anthony E. Getschman, Natasha A. Moussouras, Amanda M. Richard, Francis C. Peterson, Michael B. Dwinell, Brian F. Volkman, Richard J. Payne and Christopher T. Veldkamp
Int. J. Mol. Sci. 2017, 18(9), 1857; https://doi.org/10.3390/ijms18091857 - 25 Aug 2017
Cited by 19 | Viewed by 5320
Abstract
Chemokines are secreted proteins that direct the migration of immune cells and are involved in numerous disease states. For example, CCL21 (CC chemokine ligand 21) and CCL19 (CC chemokine ligand 19) recruit antigen-presenting dendritic cells and naïve T-cells to the lymph nodes and [...] Read more.
Chemokines are secreted proteins that direct the migration of immune cells and are involved in numerous disease states. For example, CCL21 (CC chemokine ligand 21) and CCL19 (CC chemokine ligand 19) recruit antigen-presenting dendritic cells and naïve T-cells to the lymph nodes and are thought to play a role in lymph node metastasis of CCR7 (CC chemokine receptor 7)-expressing cancer cells. For many chemokine receptors, N-terminal posttranslational modifications, particularly the sulfation of tyrosine residues, increases the affinity for chemokine ligands and may contribute to receptor ligand bias. Chemokine sulfotyrosine (sY) binding sites are also potential targets for drug development. In light of the structural similarity between sulfotyrosine and phosphotyrosine (pY), the interactions of CCL21 with peptide fragments of CCR7 containing tyrosine, pY, or sY were compared using protein NMR (nuclear magnetic resonance) spectroscopy in this study. Various N-terminal CCR7 peptides maintain binding site specificity with Y8-, pY8-, or sY8-containing peptides binding near the α-helix, while Y17-, pY17-, and sY17-containing peptides bind near the N-loop and β3-stand of CCL21. All modified CCR7 peptides showed enhanced binding affinity to CCL21, with sY having the largest effect. Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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3501 KiB  
Article
Biophysical and Computational Studies of the vCCI:vMIP-II Complex
by Anna F. Nguyen, Nai-Wei Kuo, Laura J. Showalter, Ricardo Ramos, Cynthia M. Dupureur, Michael E. Colvin and Patricia J. LiWang
Int. J. Mol. Sci. 2017, 18(8), 1778; https://doi.org/10.3390/ijms18081778 - 16 Aug 2017
Cited by 4 | Viewed by 4077
Abstract
Certain viruses have the ability to subvert the mammalian immune response, including interference in the chemokine system. Poxviruses produce the chemokine binding protein vCCI (viral CC chemokine inhibitor; also called 35K), which tightly binds to CC chemokines. To facilitate the study of vCCI, [...] Read more.
Certain viruses have the ability to subvert the mammalian immune response, including interference in the chemokine system. Poxviruses produce the chemokine binding protein vCCI (viral CC chemokine inhibitor; also called 35K), which tightly binds to CC chemokines. To facilitate the study of vCCI, we first provide a protocol to produce folded vCCI from Escherichia coli (E. coli.) It is shown here that vCCI binds with unusually high affinity to viral Macrophage Inflammatory Protein-II (vMIP-II), a chemokine analog produced by the virus, human herpesvirus 8 (HHV-8). Fluorescence anisotropy was used to investigate the vCCI:vMIP-II complex and shows that vCCI binds to vMIP-II with a higher affinity than most other chemokines, having a Kd of 0.06 ± 0.006 nM. Nuclear magnetic resonance (NMR) chemical shift perturbation experiments indicate that key amino acids used for binding in the complex are similar to those found in previous work. Molecular dynamics were then used to compare the vCCI:vMIP-II complex with the known vCCI:Macrophage Inflammatory Protein-1β/CC-Chemokine Ligand 4 (MIP-1β/CCL4) complex. The simulations show key interactions, such as those between E143 and D75 in vCCI/35K and R18 in vMIP-II. Further, in a comparison of 1 μs molecular dynamics (MD) trajectories, vMIP-II shows more overall surface binding to vCCI than does the chemokine MIP-1β. vMIP-II maintains unique contacts at its N-terminus to vCCI that are not made by MIP-1β, and vMIP-II also makes more contacts with the vCCI flexible acidic loop (located between the second and third beta strands) than does MIP-1β. These studies provide evidence for the basis of the tight vCCI:vMIP-II interaction while elucidating the vCCI:MIP-1β interaction, and allow insight into the structure of proteins that are capable of broadly subverting the mammalian immune system. Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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1119 KiB  
Article
The Effect of N-Terminal Cyclization on the Function of the HIV Entry Inhibitor 5P12-RANTES
by Anna F. Nguyen, Megan S. Schill, Mike Jian and Patricia J. LiWang
Int. J. Mol. Sci. 2017, 18(7), 1575; https://doi.org/10.3390/ijms18071575 - 20 Jul 2017
Cited by 5 | Viewed by 5966
Abstract
Despite effective treatment for those living with Human Immunodeficiency Virus (HIV), there are still two million new infections each year. Protein-based HIV entry inhibitors, being highly effective and specific, could be used to protect people from initial infection. One of the most promising [...] Read more.
Despite effective treatment for those living with Human Immunodeficiency Virus (HIV), there are still two million new infections each year. Protein-based HIV entry inhibitors, being highly effective and specific, could be used to protect people from initial infection. One of the most promising of these for clinical use is 5P12-RANTES, a variant of the chemokine RANTES/CCL5. The N-terminal amino acid of 5P12-RANTES is glutamine (Gln; called Q0), a residue that is prone to spontaneous cyclization when at the N-terminus of a protein. It is not known how this cyclization affects the potency of the inhibitor or whether cyclization is necessary for the function of the protein, although the N-terminal region of RANTES has been shown to be critical for receptor interactions, with even small changes having a large effect. We have studied the kinetics of cyclization of 5P12-RANTES as well as N-terminal variations of the protein that either produce an identical cyclized terminus (Glu0) or that cannot similarly cyclize (Asn0, Phe0, Ile0, and Leu0). We find that the half life for N-terminal cyclization of Gln is roughly 20 h at pH 7.3 at 37 °C. However, our results show that cyclization is not necessary for the potency of this protein and that several replacement terminal amino acids produce nearly-equally potent HIV inhibitors while remaining CC chemokine receptor 5 (CCR5) antagonists. This work has ramifications for the production of active 5P12-RANTES for use in the clinic, while also opening the possibility of developing other inhibitors by varying the N-terminus of the protein. Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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2794 KiB  
Article
Glycosaminoglycans Regulate CXCR3 Ligands at Distinct Levels: Protection against Processing by Dipeptidyl Peptidase IV/CD26 and Interference with Receptor Signaling
by Mieke Metzemaekers, Anneleen Mortier, Rik Janssens, Daiane Boff, Lotte Vanbrabant, Nicole Lamoen, Jo Van Damme, Mauro M. Teixeira, Ingrid De Meester, Flávio A. Amaral and Paul Proost
Int. J. Mol. Sci. 2017, 18(7), 1513; https://doi.org/10.3390/ijms18071513 - 13 Jul 2017
Cited by 27 | Viewed by 6721
Abstract
CXC chemokine ligand (CXCL)9, CXCL10 and CXCL11 direct chemotaxis of mainly T cells and NK cells through activation of their common CXC chemokine receptor (CXCR)3. They are inactivated upon NH2-terminal cleavage by dipeptidyl peptidase IV/CD26. In the present study, we found [...] Read more.
CXC chemokine ligand (CXCL)9, CXCL10 and CXCL11 direct chemotaxis of mainly T cells and NK cells through activation of their common CXC chemokine receptor (CXCR)3. They are inactivated upon NH2-terminal cleavage by dipeptidyl peptidase IV/CD26. In the present study, we found that different glycosaminoglycans (GAGs) protect the CXCR3 ligands against proteolytic processing by CD26 without directly affecting the enzymatic activity of CD26. In addition, GAGs were shown to interfere with chemokine-induced CXCR3 signaling. The observation that heparan sulfate did not, and heparin only moderately, altered CXCL10-induced T cell chemotaxis in vitro may be explained by a combination of protection against proteolytic inactivation and altered receptor interaction as observed in calcium assays. No effect of CD26 inhibition was found on CXCL10-induced chemotaxis in vitro. However, treatment of mice with the CD26 inhibitor sitagliptin resulted in an enhanced CXCL10-induced lymphocyte influx into the joint. This study reveals a dual role for GAGs in modulating the biological activity of CXCR3 ligands. GAGs protect the chemokines from proteolytic cleavage but also directly interfere with chemokine–CXCR3 signaling. These data support the hypothesis that both GAGs and CD26 affect the in vivo chemokine function. Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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2528 KiB  
Article
The Chemokine Receptor CXCR6 Evokes Reverse Signaling via the Transmembrane Chemokine CXCL16
by Vivian Adamski, Rolf Mentlein, Ralph Lucius, Michael Synowitz, Janka Held-Feindt and Kirsten Hattermann
Int. J. Mol. Sci. 2017, 18(7), 1468; https://doi.org/10.3390/ijms18071468 - 08 Jul 2017
Cited by 10 | Viewed by 5256
Abstract
Reverse signaling is a signaling mechanism where transmembrane or membrane-bound ligands transduce signals and exert biological effects upon binding of their specific receptors, enabling a bidirectional signaling between ligand and receptor-expressing cells. In this study, we address the question of whether the transmembrane [...] Read more.
Reverse signaling is a signaling mechanism where transmembrane or membrane-bound ligands transduce signals and exert biological effects upon binding of their specific receptors, enabling a bidirectional signaling between ligand and receptor-expressing cells. In this study, we address the question of whether the transmembrane chemokine (C-X-C motif) ligand 16, CXCL16 is able to transduce reverse signaling and investigate the biological consequences. For this, we used human glioblastoma cell lines and a melanoma cell line as in vitro models to show that stimulation with recombinant C-X-C chemokine receptor 6 (CXCR6) or CXCR6-containing membrane preparations induces intracellular (reverse) signaling. Specificity was verified by RNAi experiments and by transfection with expression vectors for the intact CXCL16 and an intracellularly-truncated form of CXCL16. We showed that reverse signaling via CXCL16 promotes migration in CXCL16-expressing melanoma and glioblastoma cells, but does not affect proliferation or protection from chemically-induced apoptosis. Additionally, fast migrating cells isolated from freshly surgically-resected gliomas show a differential expression pattern for CXCL16 in comparison to slowly-migrating cells, enabling a possible functional role of the reverse signaling of the CXCL16/CXCR6 pair in human brain tumor progression in vivo. Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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4658 KiB  
Article
Chemokine CXCL7 Heterodimers: Structural Insights, CXCR2 Receptor Function, and Glycosaminoglycan Interactions
by Aaron J. Brown, Prem Raj B. Joseph, Kirti V. Sawant and Krishna Rajarathnam
Int. J. Mol. Sci. 2017, 18(4), 748; https://doi.org/10.3390/ijms18040748 - 01 Apr 2017
Cited by 29 | Viewed by 5961
Abstract
Chemokines mediate diverse fundamental biological processes, including combating infection. Multiple chemokines are expressed at the site of infection; thus chemokine synergy by heterodimer formation may play a role in determining function. Chemokine function involves interactions with G-protein-coupled receptors and sulfated glycosaminoglycans (GAG). However, [...] Read more.
Chemokines mediate diverse fundamental biological processes, including combating infection. Multiple chemokines are expressed at the site of infection; thus chemokine synergy by heterodimer formation may play a role in determining function. Chemokine function involves interactions with G-protein-coupled receptors and sulfated glycosaminoglycans (GAG). However, very little is known regarding heterodimer structural features and receptor and GAG interactions. Solution nuclear magnetic resonance (NMR) and molecular dynamics characterization of platelet-derived chemokine CXCL7 heterodimerization with chemokines CXCL1, CXCL4, and CXCL8 indicated that packing interactions promote CXCL7-CXCL1 and CXCL7-CXCL4 heterodimers, and electrostatic repulsive interactions disfavor the CXCL7-CXCL8 heterodimer. As characterizing the native heterodimer is challenging due to interference from monomers and homodimers, we engineered a “trapped” disulfide-linked CXCL7-CXCL1 heterodimer. NMR and modeling studies indicated that GAG heparin binding to the heterodimer is distinctly different from the CXCL7 monomer and that the GAG-bound heterodimer is unlikely to bind the receptor. Interestingly, the trapped heterodimer was highly active in a Ca2+ release assay. These data collectively suggest that GAG interactions play a prominent role in determining heterodimer function in vivo. Further, this study provides proof-of-concept that the disulfide trapping strategy can serve as a valuable tool for characterizing the structural and functional features of a chemokine heterodimer. Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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2388 KiB  
Article
Possible Roles of CC- and CXC-Chemokines in Regulating Bovine Endometrial Function during Early Pregnancy
by Ryosuke Sakumoto, Ken-Go Hayashi, Shiori Fujii, Hiroko Kanahara, Misa Hosoe, Tadashi Furusawa and Keiichiro Kizaki
Int. J. Mol. Sci. 2017, 18(4), 742; https://doi.org/10.3390/ijms18040742 - 31 Mar 2017
Cited by 45 | Viewed by 5659
Abstract
The aim of the present study was to determine the possible roles of chemokines in regulating bovine endometrial function during early pregnancy. The expression of six chemokines, including CCL2, CCL8, CCL11, CCL14, CCL16, and CXCL10, was higher in the endometrium at 15 and [...] Read more.
The aim of the present study was to determine the possible roles of chemokines in regulating bovine endometrial function during early pregnancy. The expression of six chemokines, including CCL2, CCL8, CCL11, CCL14, CCL16, and CXCL10, was higher in the endometrium at 15 and 18 days of pregnancy than at the same days in non-pregnant animals. Immunohistochemical staining showed that chemokine receptors (CCR1, CCR2, CCR3, and CXCR3) were expressed in the epithelial cells and glandular epithelial cells of the bovine endometrium as well as in the fetal trophoblast obtained from a cow on day 18 of pregnancy. The addition of interferon-τ (IFNT) to an endometrial tissue culture system increased CCL8 and CXCL10 expression in the tissues, but did not affect CCL2, CCL11, and CCL16 expression. CCL14 expression by these tissues was inhibited by IFNT. CCL16, but not other chemokines, clearly stimulated interferon-stimulated gene 15 (ISG15) and myxovirus-resistance gene 1 (MX1) expression in these tissues. Cyclooxygenase 2 (COX2) expression decreased after stimulation with CCL8 and CCL14, and oxytocin receptor (OTR) expression was decreased by CCL2, CCL8, CCL14, and CXCL10. Collectively, the expression of chemokine genes is increased in the endometrium during early pregnancy. These genes may contribute to the regulation of endometrial function by inhibiting COX2 and OTR expression, subsequently decreasing prostaglandin production and preventing luteolysis in cows. Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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2071 KiB  
Article
Structural Basis of Native CXCL7 Monomer Binding to CXCR2 Receptor N-Domain and Glycosaminoglycan Heparin
by Aaron J. Brown, Krishna Mohan Sepuru and Krishna Rajarathnam
Int. J. Mol. Sci. 2017, 18(3), 508; https://doi.org/10.3390/ijms18030508 - 26 Feb 2017
Cited by 23 | Viewed by 5839
Abstract
CXCL7, a chemokine highly expressed in platelets, orchestrates neutrophil recruitment during thrombosis and related pathophysiological processes by interacting with CXCR2 receptor and sulfated glycosaminoglycans (GAG). CXCL7 exists as monomers and dimers, and dimerization (~50 μM) and CXCR2 binding (~10 nM) constants indicate that [...] Read more.
CXCL7, a chemokine highly expressed in platelets, orchestrates neutrophil recruitment during thrombosis and related pathophysiological processes by interacting with CXCR2 receptor and sulfated glycosaminoglycans (GAG). CXCL7 exists as monomers and dimers, and dimerization (~50 μM) and CXCR2 binding (~10 nM) constants indicate that CXCL7 is a potent agonist as a monomer. Currently, nothing is known regarding the structural basis by which receptor and GAG interactions mediate CXCL7 function. Using solution nuclear magnetic resonance (NMR) spectroscopy, we characterized the binding of CXCL7 monomer to the CXCR2 N-terminal domain (CXCR2Nd) that constitutes a critical docking site and to GAG heparin. We found that CXCR2Nd binds a hydrophobic groove and that ionic interactions also play a role in mediating binding. Heparin binds a set of contiguous basic residues indicating a prominent role for ionic interactions. Modeling studies reveal that the binding interface is dynamic and that GAG adopts different binding geometries. Most importantly, several residues involved in GAG binding are also involved in receptor interactions, suggesting that GAG-bound monomer cannot activate the receptor. Further, this is the first study that describes the structural basis of receptor and GAG interactions of a native monomer of the neutrophil-activating chemokine family. Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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Review

Jump to: Editorial, Research

1591 KiB  
Review
Chemokines from a Structural Perspective
by Michelle C. Miller and Kevin H. Mayo
Int. J. Mol. Sci. 2017, 18(10), 2088; https://doi.org/10.3390/ijms18102088 - 02 Oct 2017
Cited by 157 | Viewed by 8823
Abstract
Chemokines are a family of small, highly conserved cytokines that mediate various biological processes, including chemotaxis, hematopoiesis, and angiogenesis, and that function by interacting with cell surface G-Protein Coupled Receptors (GPCRs). Because of their significant involvement in various biological functions and pathologies, chemokines [...] Read more.
Chemokines are a family of small, highly conserved cytokines that mediate various biological processes, including chemotaxis, hematopoiesis, and angiogenesis, and that function by interacting with cell surface G-Protein Coupled Receptors (GPCRs). Because of their significant involvement in various biological functions and pathologies, chemokines and their receptors have been the focus of therapeutic discovery for clinical intervention. There are several sub-families of chemokines (e.g., CXC, CC, C, and CX3C) defined by the positions of sequentially conserved cysteine residues. Even though all chemokines also have a highly conserved, three-stranded β-sheet/α-helix tertiary structural fold, their quarternary structures vary significantly with their sub-family. Moreover, their conserved tertiary structures allow for subunit swapping within and between sub-family members, thus promoting the concept of a “chemokine interactome”. This review is focused on structural aspects of CXC and CC chemokines, their functional synergy and ability to form heterodimers within the chemokine interactome, and some recent developments in structure-based chemokine-targeted drug discovery. Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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2219 KiB  
Review
Regulation of Chemokine Function: The Roles of GAG-Binding and Post-Translational Nitration
by Sarah Thompson, Beatriz Martínez-Burgo, Krishna Mohan Sepuru, Krishna Rajarathnam, John A. Kirby, Neil S. Sheerin and Simi Ali
Int. J. Mol. Sci. 2017, 18(8), 1692; https://doi.org/10.3390/ijms18081692 - 03 Aug 2017
Cited by 27 | Viewed by 8505
Abstract
The primary function of chemokines is to direct the migration of leukocytes to the site of injury during inflammation. The effects of chemokines are modulated by several means, including binding to G-protein coupled receptors (GPCRs), binding to glycosaminoglycans (GAGs), and through post-translational modifications [...] Read more.
The primary function of chemokines is to direct the migration of leukocytes to the site of injury during inflammation. The effects of chemokines are modulated by several means, including binding to G-protein coupled receptors (GPCRs), binding to glycosaminoglycans (GAGs), and through post-translational modifications (PTMs). GAGs, present on cell surfaces, bind chemokines released in response to injury. Chemokines bind leukocytes via their GPCRs, which directs migration and contributes to local inflammation. Studies have shown that GAGs or GAG-binding peptides can be used to interfere with chemokine binding and reduce leukocyte recruitment. Post-translational modifications of chemokines, such as nitration, which occurs due to the production of reactive species during oxidative stress, can also alter their biological activity. This review describes the regulation of chemokine function by GAG-binding ability and by post-translational nitration. These are both aspects of chemokine biology that could be targeted if the therapeutic potential of chemokines, like CXCL8, to modulate inflammation is to be realised. Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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2126 KiB  
Review
Mechanisms of Regulation of the Chemokine-Receptor Network
by Martin J. Stone, Jenni A. Hayward, Cheng Huang, Zil E. Huma and Julie Sanchez
Int. J. Mol. Sci. 2017, 18(2), 342; https://doi.org/10.3390/ijms18020342 - 07 Feb 2017
Cited by 191 | Viewed by 13491
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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