Crystal Structures of Oligomeric Forms of the IP-10/CXCL10 Chemokine

Swaminathan, Ganesh; Holloway, Daniel E.; Colvin, Richard A.; Campanella, Gabriele K.; Papageorgiou, Anastassios C.; Luster, Andrew D.; Acharya, K. Ravi

doi:10.1016/s0969-2126(03)00070-4

Cited by 74 publications

(87 citation statements)

References 57 publications

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“…These results indicate that, in vitro, a considerably higher concentration of monomer mutant CXCL10 ligand is required to bind receptor CXCR3 and heparin (34). In an experiment designed by Swaminathan et al (3), CXCL10 molecules were found to exist in three different crystal forms: monomer, dimer and tetramer. In free solution, CXCL10 exists in monomer-dimer equilibrium, and tetrameric structures may represent species promoted by the binding of glycosaminoglycans (GAG).…”

Section: Cxcl10 Gene Structure Function and Signaling Pathwaysmentioning

confidence: 94%

“…Based on the position of the first two conserved cysteine residues within the N-terminal, the chemokines are divided into two major (CX3C and CXC) and two minor (CC and C) subfamilies (2)(3)(4). The CX3C subfamily has three intervening residues separating the two N-terminal cysteines, whereas the CXC subfamily only has one non-conserved amino acid residue separating the N-terminal cysteines.…”

Section: Introductionmentioning

confidence: 99%

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The emerging role of CXCL10 in cancer (Review)

2011

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Abstract. The chemokine interferon-γ inducible protein 10 kDa (CXCL10) is a member of the CXC chemokine family which binds to the CXCR3 receptor to exert its biological effects. CXCL10 is involved in chemotaxis, induction of apoptosis, regulation of cell growth and mediation of angiostatic effects. CXCL10 is associated with a variety of human diseases including infectious diseases, chronic inflammation, immune dysfuntion, tumor development, metastasis and dissemination. More importantly, CXCL10 has been identified as a major biological marker mediating disease severity and may be utilized as a prognostic indicator for various diseases. In this review, we focus on current research elucidating the emerging role of CXCL10 in the pathogenesis of cancer. Understanding the role of CXCL10 in disease initiation and progression may provide the basis for developing CXCL10 as a potential biomarker and therapeutic target for related human malignancies.

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Section: Cxcl10 Gene Structure Function and Signaling Pathwaysmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

The emerging role of CXCL10 in cancer (Review)

2011

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“…The CXCL10 crystal structure was recently determined (30), and the structural domains of CXCL10 protein have been investigated by mutational studies (31,32). The N-terminal arginine residue of CXCL10 protein, preceding the first cysteine, is important for CXCR3 signaling, whereas mutations of the 4 basic residues of the C-terminal helix (K71E/R72Q/K74Q/R75E) combined with the R22A mutation (CtR22A) abolish most of the heparin-binding activity of CXCL10 (32).…”

Section: Figurementioning

confidence: 99%

Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4

Jiang¹,

Liang²,

Campanella³

et al. 2010

J. Clin. Invest.

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151

130

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Pulmonary fibrosis is a progressive, dysregulated response to injury culminating in compromised lung function due to excess extracellular matrix production. The heparan sulfate proteoglycan syndecan-4 is important in mediating fibroblast-matrix interactions, but its role in pulmonary fibrosis has not been explored. To investigate this issue, we used intratracheal instillation of bleomycin as a model of acute lung injury and fibrosis. We found that bleomycin treatment increased syndecan-4 expression. Moreover, we observed a marked decrease in neutrophil recruitment and an increase in both myofibroblast recruitment and interstitial fibrosis in bleomycin-treated syndecan-4-null (Sdc4 -/-) mice. Subsequently, we identified a direct interaction between CXCL10, an antifibrotic chemokine, and syndecan-4 that inhibited primary lung fibroblast migration during fibrosis; mutation of the heparin-binding domain, but not the CXCR3 domain, of CXCL10 diminished this effect. Similarly, migration of fibroblasts from patients with pulmonary fibrosis was inhibited in the presence of CXCL10 protein defective in CXCR3 binding. Furthermore, administration of recombinant CXCL10 protein inhibited fibrosis in WT mice, but not in Sdc4 -/-mice. Collectively, these data suggest that the direct interaction of syndecan-4 and CXCL10 in the lung interstitial compartment serves to inhibit fibroblast recruitment and subsequent fibrosis. Thus, administration of CXCL10 protein defective in CXCR3 binding may represent a novel therapy for pulmonary fibrosis.

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“…Chemokines are small (8)(9)(10)(11)(12), secreted proteins that have critical roles in many biological processes, including lymphoid trafficking and inflammation, angiogenesis/angiostasis, and development, as well as in many disease states (1,2). Based on the pattern of N-terminal cysteine residues, they have been categorized into CC, CXC, C, and CX 3 C families.…”

mentioning

confidence: 99%

Heterodimerization of CCR2 Chemokines and Regulation by Glycosaminoglycan Binding

Crown

Sweeney

et al. 2006

Journal of Biological Chemistry

100

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Despite the wide range of sequence diversity among chemokines, their tertiary structures are remarkably similar. Furthermore, many chemokines form dimers or higher order oligomers, but all characterized oligomeric structures are based primarily on two dimerization motifs represented by CC-chemokine or CXC-chemokine dimer interfaces. These observations raise the possibility that some chemokines could form unique hetero-oligomers using the same oligomerization motifs. Such interactions could modulate the overall signaling response of the receptors, thereby providing a general mechanism for regulating chemokine function. For some chemokines, homo-oligomerization has also been shown to be coupled to glycosaminoglycan (GAG)-binding. However, the effect of GAG binding on chemokine hetero-oligomerization has not yet been demonstrated. In this report, we characterized the heterodimerization of the CCR2 ligands MCP-1 (CCL2), MCP-2 (CCL8), MCP-3 (CCL7), MCP-4 (CCL13), and eotaxin (CCL11), as well as the effects of GAG binding, using electrospray ionization Fourier transform ion cyclotron resonance (ESI-FTICR) mass spectrometry. Strong heterodimerization was observed between CCL2 and CCL8 at the expense of homodimer formation. Using NMR, we showed that the heterodimer is predominant in solution and forms a specific CC chemokine-like dimer. By contrast, only moderate heterodimer formation was observed between CCL2⅐CCL13, CCL2⅐CCL11 and CCL8⅐CCL13, and no heterodimerization was observed when any other CCR2 ligand was added to CCL7. To investigate the effect of a highly sulfated GAG on the formation of heterodimers, each chemokine pair was mixed with the heparin pentasaccharide, Arixtra, and assayed by ESI-FTICR mass spectrometry. Although no CCL8⅐CCL11 heterodimer was observed in the absence of GAG, abundant ions corresponding to the ternary complex, CCL8⅐CCL11⅐Arixtra, were observed upon addition of Arixtra. Heterodimerization between CCL2 and CCL11 was also enhanced in the presence of Arixtra. In summary, these results indicate that some CCR2 ligands can form stable heterodimers in preference to homodimers and that these interactions, like those of homo-oligomers, can be influenced by some GAGs.

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Crystal Structures of Oligomeric Forms of the IP-10/CXCL10 Chemokine

Cited by 74 publications

References 57 publications

The emerging role of CXCL10 in cancer (Review)

The emerging role of CXCL10 in cancer (Review)

Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4

Heterodimerization of CCR2 Chemokines and Regulation by Glycosaminoglycan Binding

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