Neutrophil-activating Peptide-2 and Melanoma Growth-stimulatory Activity Are Functional as Monomers for Neutrophil Activation

Rajarathnam, Krishna; Kay, Cyril M.; Dewald, Béatrice; Wolf, Marlene; Baggiolini, Marco; Clark‐Lewis, Ian; Sykes, Brian D.

doi:10.1074/jbc.272.3.1725

Cited by 46 publications

(47 citation statements)

References 41 publications

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“…Structure determination indicates that many chemokines dimerize, and the observation that chemokine dimerization is also coupled to binding to GAGs suggests that all chemokines form dimers and/or higher order oligomers (21,22). Monomeric mutants of CXC and CC chemokines observed as dimers and tetramers in NMR and x-ray structures show the same activity as the native protein, indicating unambiguously that a monomer is competent for receptor function (11,(23)(24)(25). Whether the dimeric form is competent for receptor function has been less clear.…”

Section: Il-8 Dimer Does Not Bind Cxcr1 Receptor 36177mentioning

confidence: 90%

Dimer Dissociation Is Essential for Interleukin-8 (IL-8) Binding to CXCR1 Receptor

Fernando

Chin

Rösgen

et al. 2004

Journal of Biological Chemistry

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Chemokines play a fundamental role in trafficking of immune cells and in host defense against infection. The role of chemokines in the recruitment process is highly regulated spatially and temporally and involves interactions with G protein-coupled receptors and cell surface glycosaminoglycans. The dynamic equilibrium between chemokine monomers and dimers, both free in solution and in cell surface-bound forms, regulates different components of recruitment such as chemotaxis and receptor signaling. The binding and activity of the chemokine interleukin-8 (IL-8) for its receptors, previously studied using "trapped" non-associating monomers and non-dissociating dimers, show that the monomer has a native-like function but support conflicting roles for the dimer. We have measured the binding of native IL-8 to the CXCR1 N-domain, using isothermal titration calorimetry and sedimentation equilibrium techniques. The N-domain constitutes a critical binding site, and IL-8 binding affinity to the receptor N-domain is in the same concentration range as the IL-8 monomerdimer equilibrium. We observed that only the IL-8 monomer, and not the dimer, is competent in binding the receptor N-domain. Based on our results, we propose that IL-8 dimerization functions as a negative regulator for the receptor function and as a positive regulator for binding to glycosaminoglycans and that both play a role in the neutrophil recruitment process.

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Section: Il-8 Dimer Does Not Bind Cxcr1 Receptor 36177mentioning

confidence: 90%

Dimer Dissociation Is Essential for Interleukin-8 (IL-8) Binding to CXCR1 Receptor

Fernando

Chin

Rösgen

et al. 2004

Journal of Biological Chemistry

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“…Many chemokines form homodimers or oligomers at high nanomolar to micromolar concentrations (36-39) whereas others exist strictly as monomers (40)(41)(42)(43)(44). For IL-8, MCP-1, MCP-2, and I-309, the monomeric form predominates in solution at physiological (nM) concentrations (32,44,45).…”

Section: Vv-35kda Protein Monomer Binds Monomeric Mcp-1mentioning

confidence: 99%

“…For IL-8, MCP-1, MCP-2, and I-309, the monomeric form predominates in solution at physiological (nM) concentrations (32,44,45). Furthermore, several studies have shown that monomeric variants of chemokines are able to efficiently bind and activate their host receptors, suggesting that the monomer is the physiologically relevant form with respect to chemotaxis (32,41,46,47). Among these studies, it was shown that an obligate monomeric variant of MCP-1 containing a mutation of proline at position 8 to alanine (P8A) induces chemotaxis of monocytes as potently as wtMCP-1 (32).…”

Section: Vv-35kda Protein Monomer Binds Monomeric Mcp-1mentioning

confidence: 99%

Molecular determinants for CC-chemokine recognition by a poxvirus CC-chemokine inhibitor

Seet

Singh

Paavola

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Poxviruses express a family of secreted proteins that bind with high affinity to chemokines and antagonize the interaction with their cognate G protein-coupled receptors (GPCRs). These viral inhibitors are novel in structure and, unlike cellular chemokine receptors, are able to specifically interact with most, if not all, CC-chemokines. We therefore sought to define the structural features of CC-chemokines that facilitate this broad-spectrum interaction. Here, we identify the residues present on human monocyte chemoattractant protein-1 (MCP-1) that are required for highaffinity interaction with the vaccinia virus 35-kDa CC-chemokine binding protein (VV-35kDa). Not only do these residues correspond to those required for interaction with the cognate receptor CCR2b but they are also conserved among many CC-chemokines. Thus, the results provide a structural basis for the ability of VV-35kDa to promiscuously recognize CC-chemokines and block binding to their receptors.CCR2b ͉ chemokine binding protein ͉ monocyte chemoattractant protein-1 ͉ mutagenesis ͉ surface plasmon resonance

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“…Sedimentation Equilibrium Ultracentrifugation-Sedimentation equilibrium studies were carried out on a Beckman Spinco model E analytical ultracentrifuge using Raleigh absorbance optics as described (16). Sedimentation equilibrium runs of eotaxin were performed at a concentration of ϳ1 mg/ml in 100 mM NaCl, 50 mM sodium phosphate, pH 5.0 and 7.0.…”

Section: Chemical Synthesis Of Eotaxin-eotaxinmentioning

confidence: 99%

“…Following the first eight residues which contain no defined structure, the first disulfide is undefined, whereas the second adopts a left-handed spiral. The loop (N-loop, residues [11][12][13][14][15][16][17][18][19] contains a bend at residue 16 and leads into a 3/10 helix (residues 19 -22). Strand ␤1 contains a ␤-bulge at residue Glu-24 and extends from residues Ser-25 to Ile-29.…”

mentioning

confidence: 99%

Solution Structure of Eotaxin, a Chemokine That Selectively Recruits Eosinophils in Allergic Inflammation

Crump¹,

Rajarathnam²,

Kim³

et al. 1998

Journal of Biological Chemistry

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103

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The solution structure of the CCR3-specific chemokine, eotaxin, has been determined by NMR spectroscopy. The quaternary structure of eotaxin was investigated by ultracentrifugation and NMR, and it was found to be in equilibrium between monomer and dimer under a wide range of conditions. At pH < 5 and low ionic strength, eotaxin was found to be predominantly a monomer. The three-dimensional structure of the eotaxin monomer solved at pH 5.0 revealed that it has a typical chemokine fold, which includes a 3-stranded ␤-sheet and an overlying ␣-helix. Except for the N-terminal residues (residues 1-8), the core of the protein is well defined. The eotaxin structure is compared with the chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES) and monocyte chemoattractant protein-1 (MCP-1); eotaxin binds only CC chemokine receptor CCR3, whereas RANTES binds many receptors including CCR3, and MCP-1 binds a distinct receptor, CCR2. The RMSD of the eotaxin ensemble of structures with the RANTES average minimized monomeric subunit is 5.52 ؎ 0.87 Å over all backbone atoms and 1.14 ؎ 0.09 Å over backbone atoms of residues 11-28 and 34 -65. The most important difference between the structures is in the N-terminal residues that are unstructured in eotaxin but structured in RANTES and MCP-1. Several residues in the loop region of RANTES show similar packing in eotaxin (residues 11-17). As the N-terminal and loop regions have been shown to be critical for receptor binding and signaling, this structure will be useful for determining the basis for CCR3 selectivity of the eotaxin.Eotaxin (1, 2) is a member of the chemoattractant cytokine (chemokine) family of proteins that mediates the migration and accumulation of eosinophils at sites of parasitic infection and allergic response (3-5). The chemokines play a pivotal role in the control of leukocyte chemotaxis and represent attractive targets for the blockade of inflammatory disease progression. Eotaxin belongs to the CC chemokine family which is distinguished by the presence of two adjacent cysteines close to the N terminus (6). The CC chemokines activate a wide range of leukocytes including eosinophils, basophils, monocytes, dendritic cells, and T lymphocytes. Chemokine activities are mediated through the binding and activation of seven transmembrane helix G-coupled receptors (6), and eight distinct functional CC chemokine receptors have been identified (6 -9). Their broad leukocyte distribution coupled with a lack of CC chemokine specificity means there is generally considerable redundancy among the CC chemokine family. However, the cloning and characterization of eotaxin and the related protein eotaxin-2 (10) and its receptor CCR3 1 (11) has revealed its unique and most important feature, a high selectivity for eosinophils (1, 2). Eotaxin has been implicated as the predominant chemokine in the recruitment of eosinophils and the eosinophil-mediated tissue damage associated with asthma. Thus eotaxin is a possible target for anti-asthmatic drugs.The three-di...

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Neutrophil-activating Peptide-2 and Melanoma Growth-stimulatory Activity Are Functional as Monomers for Neutrophil Activation

Cited by 46 publications

References 41 publications

Dimer Dissociation Is Essential for Interleukin-8 (IL-8) Binding to CXCR1 Receptor

Dimer Dissociation Is Essential for Interleukin-8 (IL-8) Binding to CXCR1 Receptor

Molecular determinants for CC-chemokine recognition by a poxvirus CC-chemokine inhibitor

Solution Structure of Eotaxin, a Chemokine That Selectively Recruits Eosinophils in Allergic Inflammation

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