Platelet-Derived Chemokine CXCL7 Dimer Preferentially Exists in the Glycosaminoglycan-Bound Form: Implications for Neutrophil–Platelet Crosstalk
Platelet-derived chemokine CXCL7 (also known as NAP-2) plays a crucial role in orchestrating neutrophil recruitment in response to vascular injury. CXCL7 exerts its function by activating the CXC chemokine receptor 2 (CXCR2) receptor and binding sulfated glycosaminoglycans (GAGs) that regulate recep...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01248/full |
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| author | Aaron J. Brown Aaron J. Brown Krishna Mohan Sepuru Krishna Mohan Sepuru Kirti V. Sawant Krishna Rajarathnam Krishna Rajarathnam Krishna Rajarathnam |
| author_facet | Aaron J. Brown Aaron J. Brown Krishna Mohan Sepuru Krishna Mohan Sepuru Kirti V. Sawant Krishna Rajarathnam Krishna Rajarathnam Krishna Rajarathnam |
| author_sort | Aaron J. Brown |
| collection | DOAJ |
| description | Platelet-derived chemokine CXCL7 (also known as NAP-2) plays a crucial role in orchestrating neutrophil recruitment in response to vascular injury. CXCL7 exerts its function by activating the CXC chemokine receptor 2 (CXCR2) receptor and binding sulfated glycosaminoglycans (GAGs) that regulate receptor activity. CXCL7 exists as monomers, dimers, and tetramers, and previous studies have shown that the monomer dominates at lower and the tetramer at higher concentrations. These observations then raise the question: what, if any, is the role of the dimer? In this study, we make a compelling observation that the dimer is actually the favored form in the GAG-bound state. Further, we successfully characterized the structural basis of dimer binding to GAG heparin using solution nuclear magnetic resonance (NMR) spectroscopy. The chemical shift assignments were obtained by exploiting heparin binding-induced NMR spectral changes in the WT monomer and dimer and also using a disulfide-linked obligate dimer. We observe that the receptor interactions of the dimer are similar to the monomer and that heparin-bound dimer is occluded from receptor interactions. Cellular assays also show that the heparin-bound CXCL7 is impaired for CXCR2 activity. We conclude that the dimer–GAG interactions play an important role in neutrophil–platelet crosstalk, and that these interactions regulate gradient formation and the availability of the free monomer for CXCR2 activation and intrathrombus neutrophil migration to the injury site. |
| first_indexed | 2024-04-12T05:45:21Z |
| format | Article |
| id | doaj.art-5ccc58a30a744d99a02ec781ccb4a591 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T05:45:21Z |
| publishDate | 2017-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5ccc58a30a744d99a02ec781ccb4a5912022-12-22T03:45:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-10-01810.3389/fimmu.2017.01248291515Platelet-Derived Chemokine CXCL7 Dimer Preferentially Exists in the Glycosaminoglycan-Bound Form: Implications for Neutrophil–Platelet CrosstalkAaron J. Brown0Aaron J. Brown1Krishna Mohan Sepuru2Krishna Mohan Sepuru3Kirti V. Sawant4Krishna Rajarathnam5Krishna Rajarathnam6Krishna Rajarathnam7Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, United StatesSealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, United StatesDepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, United StatesSealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, United StatesDepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, United StatesDepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, United StatesSealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, United StatesDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United StatesPlatelet-derived chemokine CXCL7 (also known as NAP-2) plays a crucial role in orchestrating neutrophil recruitment in response to vascular injury. CXCL7 exerts its function by activating the CXC chemokine receptor 2 (CXCR2) receptor and binding sulfated glycosaminoglycans (GAGs) that regulate receptor activity. CXCL7 exists as monomers, dimers, and tetramers, and previous studies have shown that the monomer dominates at lower and the tetramer at higher concentrations. These observations then raise the question: what, if any, is the role of the dimer? In this study, we make a compelling observation that the dimer is actually the favored form in the GAG-bound state. Further, we successfully characterized the structural basis of dimer binding to GAG heparin using solution nuclear magnetic resonance (NMR) spectroscopy. The chemical shift assignments were obtained by exploiting heparin binding-induced NMR spectral changes in the WT monomer and dimer and also using a disulfide-linked obligate dimer. We observe that the receptor interactions of the dimer are similar to the monomer and that heparin-bound dimer is occluded from receptor interactions. Cellular assays also show that the heparin-bound CXCL7 is impaired for CXCR2 activity. We conclude that the dimer–GAG interactions play an important role in neutrophil–platelet crosstalk, and that these interactions regulate gradient formation and the availability of the free monomer for CXCR2 activation and intrathrombus neutrophil migration to the injury site.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01248/fullchemokineglycosaminoglycanheparinNMRCXCL7NAP-2 |
| spellingShingle | Aaron J. Brown Aaron J. Brown Krishna Mohan Sepuru Krishna Mohan Sepuru Kirti V. Sawant Krishna Rajarathnam Krishna Rajarathnam Krishna Rajarathnam Platelet-Derived Chemokine CXCL7 Dimer Preferentially Exists in the Glycosaminoglycan-Bound Form: Implications for Neutrophil–Platelet Crosstalk Frontiers in Immunology chemokine glycosaminoglycan heparin NMR CXCL7 NAP-2 |
| title | Platelet-Derived Chemokine CXCL7 Dimer Preferentially Exists in the Glycosaminoglycan-Bound Form: Implications for Neutrophil–Platelet Crosstalk |
| title_full | Platelet-Derived Chemokine CXCL7 Dimer Preferentially Exists in the Glycosaminoglycan-Bound Form: Implications for Neutrophil–Platelet Crosstalk |
| title_fullStr | Platelet-Derived Chemokine CXCL7 Dimer Preferentially Exists in the Glycosaminoglycan-Bound Form: Implications for Neutrophil–Platelet Crosstalk |
| title_full_unstemmed | Platelet-Derived Chemokine CXCL7 Dimer Preferentially Exists in the Glycosaminoglycan-Bound Form: Implications for Neutrophil–Platelet Crosstalk |
| title_short | Platelet-Derived Chemokine CXCL7 Dimer Preferentially Exists in the Glycosaminoglycan-Bound Form: Implications for Neutrophil–Platelet Crosstalk |
| title_sort | platelet derived chemokine cxcl7 dimer preferentially exists in the glycosaminoglycan bound form implications for neutrophil platelet crosstalk |
| topic | chemokine glycosaminoglycan heparin NMR CXCL7 NAP-2 |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01248/full |
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