| First Author | Rajasekaran D | Year | 2012 |
| Journal | Biochemistry | Volume | 51 |
| Issue | 28 | Pages | 5642-54 |
| PubMed ID | 22686371 | Mgi Jnum | J:188844 |
| Mgi Id | MGI:5442451 | Doi | 10.1021/bi3001566 |
| Citation | Rajasekaran D, et al. (2012) A model of GAG/MIP-2/CXCR2 interfaces and its functional effects. Biochemistry 51(28):5642-54 |
| abstractText | MIP-2/CXCL2 is a murine chemokine related to human chemokines that possesses the Glu-Leu-Arg (ELR) activation motif and activates CXCR2 for neutrophil chemotaxis. We determined the structure of MIP-2 to 1.9 A resolution and created a model with its murine receptor CXCR2 based on the coordinates of human CXCR4. Chemokine-induced migration of cells through specific G-protein coupled receptors is regulated by glycosaminoglycans (GAGs) that oligomerize chemokines. MIP-2 GAG-binding residues were identified that interact with heparin disaccharide I-S by NMR spectroscopy. A model GAG/MIP-2/CXCR2 complex that supports a 2:2 complex between chemokine and receptor was created. Mutants of these disaccharide-binding residues were made and tested for heparin binding, in vitro neutrophil chemotaxis, and in vivo neutrophil recruitment to the mouse peritoneum and lung. The mutants have a 10-fold decrease in neutrophil chemotaxis in vitro. There is no difference in neutrophil recruitment between wild-type MIP-2 and mutants in the peritoneum, but all activity of the mutants is lost in the lung, supporting the concept that GAG regulation of chemokines is tissue-dependent. |
