| Literature DB >> 22686371 |
Deepa Rajasekaran1, Camille Keeler, Mansoor A Syed, Matthew C Jones, Jeffrey K Harrison, Dianqing Wu, Vineet Bhandari, Michael E Hodsdon, Elias J Lolis.
Abstract
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 Å 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.Entities:
Mesh：
Substances：
Year: 2012 PMID： 22686371 PMCID： PMC3511906 DOI： 10.1021/bi3001566
Source DB: PubMed Journal: Biochemistry ISSN： 0006-2960 Impact factor: 3.162