Interleukin 8, Neutrophil-Activating Peptide-2 and GRO-α Bind to and Elicit Cell Activation via Specific and Different Amino Acid Residues of CXCR2

Katancik, James A.; Sharma, Ashu; Nardin, Ernesto De

doi:10.1006/cyto.2000.0742

Cited by 62 publications

(58 citation statements)

References 31 publications

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“…Although being beyond the scope of the present study, this may be suggestive of a conserved determinant for arrestin recruitment in chemokine receptors. Indeed, Lys-3.26 is highly conserved in chemokine receptors, and corresponding mutants in CXCR2 and CCR7 were found unable to signal via G proteins (43,44). It is possible, although not reported, that these mutants constitutively recruit arrestin, i.e.…”

Section: Discussionmentioning

confidence: 99%

Mutational Analysis of Atypical Chemokine Receptor 3 (ACKR3/CXCR7) Interaction with Its Chemokine Ligands CXCL11 and CXCL12

Benredjem

Girard

Rhainds

et al. 2017

Journal of Biological Chemistry

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Edited by Henrik G. DohlmanAtypical chemokine receptors do not mediate chemotaxis or G protein signaling, but they recruit arrestin. They also efficiently scavenge their chemokine ligands, thereby contributing to gradient maintenance and termination. ACKR3, also known as CXCR7, binds and degrades the constitutive chemokine CXCL12, which also binds the canonical receptor CXCR4, and CXCL11, which also binds CXCR3. Here we report comprehensive mutational analysis of the ACKR3 interaction with its chemokine ligands, using 30 substitution mutants. Atypical chemokine receptors (ACKRs)4 are chemokine receptors that do not activate G protein-dependent signaling cascades upon agonist binding; they also do not mediate chemotaxis (1). Rather, chemokine binding to ACKRs leads to rapid chemokine internalization and degradation. Therefore, ACKRs act as chemokine scavengers and play a role in chemokine gradient reshaping, maintenance, and resolution.ACKR3, also known as CXCR7, is an atypical chemokine receptor for the constitutive chemokine CXCL12 (SDF-1), which also binds CXCR4 as a cognate canonical chemokine receptor (2). The second ACKR3 ligand is the highly regulated inflammatory chemokine CXCL11 (I-TAC), which also binds the canonical receptor CXCR3. Being unable to raise G protein responses in most cell types, agonist binding to ACKR3 nevertheless induces arrestin recruitment as a signaling response (3) and rapid degradation of both CXCL12 and CXCL11 (4). ACKR3 has been identified as a potentially promising drug target (2). Given the highly divergent role and regulation of its two ligands, selective interference with their ACKR3 interaction and scavenging may be of interest, warranting better understanding of ligand engagement and scavenging.The structures of chemokine receptors are beginning to be unraveled by crystallography, and the results are in line with those reported earlier from receptor mutagenesis-based approaches (5-7). The reported chemokine receptor crystals required co-crystallization in complex with receptor antagonists. CXCR4 was the first receptor crystallized in complex with an antagonistic chemokine ligand, the virally encoded vMIP-II, which has also permitted refined modeling of the putative CXCR4-CXCL12 complex (8). Overall, these structures refine an early two-step binding model that provides a conceptual framework for the interactions of chemokines with canonical chemokine receptors (for a recent critical review of this model see Kleist et al.; Ref. 9). Following this model, initial chemokine interaction with the receptor critically depends on the receptor N terminus, and some extracellular loop residues. This is then followed by secondary interaction mainly involving the chemokine N terminus with receptor binding pocket residues; this second interaction is required for receptor activation. Of note, for CXCR4 the two-step interaction model is supported by 4 The abbreviations used are: ACKR, atypical chemokine receptor; BRET, bioluminescence resonance energy transfer; CRS1, chemokine recognition...

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Section: Discussionmentioning

confidence: 99%

Mutational Analysis of Atypical Chemokine Receptor 3 (ACKR3/CXCR7) Interaction with Its Chemokine Ligands CXCL11 and CXCL12

Benredjem

Girard

Rhainds

et al. 2017

Journal of Biological Chemistry

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“…For example, CCR1 can bind approximately ten ligands with high affinity and CCR3 up to 15 ligands. In addition, there is emerging evidence that these ligands do not all interact in a fully redundant manner with their receptors [14][15][16] potentially allowing for exquisite subtlety and complexity of control via these receptors and their varied ligands. In addition to receptor promiscuity, many of the ligands are unfaithful in that they can bind to multiple receptors with high affinity.…”

Section: Chemokine Receptorsmentioning

confidence: 99%

D6 and the atypical chemokine receptor family: Novel regulators of immune and inflammatory processes

2009

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Chemokines are key regulators of leukocyte migration and play important roles in a number of physiological and pathological immune and inflammatory contexts. In addition to the classical signalling chemokine receptors there has emerged, recently, a new subclass of atypical chemokine receptors. This subfamily is characterised by an apparent lack of signalling and, in some cases, by an ability to internalise and degrade chemokine ligands. This review describes the family of atypical chemokine receptors with particular emphasis on the D6 receptor. The in vitro and in vivo biology of D6 is described, which indicates that D6 is active as a scavenger of inflammatory CC-chemokines and appears to play essential roles in the regulation of inflammatory responses.Key words: Chemokines . Immune regulation . Inflammation IntroductionThe movement of leukocytes during immune and inflammatory responses is a carefully orchestrated process that ensures coordinated cellular migration in response to physiological and pathological cues. Prominent amongst the regulators of leukocyte movement are the members of the chemokine family [1]. Chemokines are small proteins (8-12 kDa) and membership of the chemokine family is defined on the basis of the presence of variations on a conserved cysteine motif in the mature section of the proteins. Chemokines can be assigned to one of four subfamilies according to the specific nature of this motif. The majority of chemokines have four cysteines with 28 chemokines being assigned to the CC family (so-called because of the juxtaposition of the first two cysteine residues) and 16 being assigned to the CXC family (which possess a single variable amino acid between the first two cysteines). The two smaller subfamilies are represented by single members and are the CX3C family (three amino acids between the first two cyteines) and the XC family, which lacks the first and third cyteines seen in the other family members. Much confusion arose in the mid-1990s due to the complex and variable nomenclature used to refer to chemokines. For this reason a systematic nomenclature system has been adopted, which refers to the chemokines as ligands of each of the subfamilies and numbers them according to when their sequences were first deposited in the Genbank databases [2]. Thus, CCL1 is the first CC chemokine to be identified and CCL28 the most recent. Chemokines and their roles in leukocyte migrationFunctionally, chemokines are known to be pleiotropic. However, their main role is in the regulation of leukocyte migration. In this context we can define chemokines as being either homeostatic/ constitutive or inflammatory according to the contexts in which they function [2,3]. Homeostatic chemokinesThe homeostatic chemokines are important for the regulation of basal leukocyte trafficking and regulate processes such as the Mini-Reviewtissue-specific migration of T cells and the homing of DC to draining lymph nodes [4][5][6]. In combination with adhesion molecules, the homeostatic chemokines can form part of a very spec...

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“…Site I contributes predominantly to receptor selectivity and affinity, whereas site II binding stabilizes the receptor conformation to elicit signaling responses. 66,67 Regions involved in the high affinity ligand binding and activation of CXCR2 have been mapped using chimeric receptors, 68,69 peptide competition studies, 70 site directed mutagenesis, 71 dynamic molecular modeling 72 and investigation of residues that may contribute to species differences in ligand affinity. 73 These studies have widely implicated the N-terminus of the receptor in high affinity binding of ligands, but residues across the extracellular loops have also been shown to be involved.…”

Section: Discussionmentioning

confidence: 99%

“…69,70,74 Ahuja et al 69 demonstrated functional responses from CXCR2 www.landesbioscience.comligands in a CXCR2 chimeric receptor containing a CCR1 N-terminus in the absence of high affinity ligand binding and point mutations in ECL1 have been shown to have no effect on Gro-a binding, but to inhibit calcium signaling. 71 In addition, the domains involved in binding are ligand dependent as demonstrated by mapping of IL-8, Gro-a and NAP-2. 71 Therefore, antibodies to CXCR2 could have ligand dependent effects due to the different interaction sites of the ligands with the receptor and block signaling, but not ligand binding as has been shown for CXCR1.…”

Section: Discussionmentioning

confidence: 99%

“…71 In addition, the domains involved in binding are ligand dependent as demonstrated by mapping of IL-8, Gro-a and NAP-2. 71 Therefore, antibodies to CXCR2 could have ligand dependent effects due to the different interaction sites of the ligands with the receptor and block signaling, but not ligand binding as has been shown for CXCR1. 75 The minimal epitopes for several neutralizing anti-human CXCR2 monoclonal antibodies generated from immunization of mice with human CXCR2 overexpressing cell lines have been described as the N-terminal sequence 'FEDFW'.…”

Section: Discussionmentioning

confidence: 99%

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Phage display and hybridoma generation of antibodies to human CXCR2 yields antibodies with distinct mechanisms and epitopes

Rossant

Carroll²,

Huang

et al. 2014

mAbs

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Interleukin 8, Neutrophil-Activating Peptide-2 and GRO-α Bind to and Elicit Cell Activation via Specific and Different Amino Acid Residues of CXCR2

Cited by 62 publications

References 31 publications

Mutational Analysis of Atypical Chemokine Receptor 3 (ACKR3/CXCR7) Interaction with Its Chemokine Ligands CXCL11 and CXCL12

Mutational Analysis of Atypical Chemokine Receptor 3 (ACKR3/CXCR7) Interaction with Its Chemokine Ligands CXCL11 and CXCL12

D6 and the atypical chemokine receptor family: Novel regulators of immune and inflammatory processes

Phage display and hybridoma generation of antibodies to human CXCR2 yields antibodies with distinct mechanisms and epitopes

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