The goal of the proposed research is to understand at the molecular level, how chemokines and their receptors control leukocyte migration. These proteins are critical to the normal functioning of the immune system, but they are also involved in a large number of diseases including inflammation, atherosclerosis, and viral disease. Furthermore, it has been shown that chemokine receptors serve as obligate coreceptors for fusion of the human immuno-deficiency virus with leukocytes, and that viral infectivity can be inhibited by the ligands of the coreceptors. Thus there are a wide range of clinically important diseases motivating our studies of chemokine function. Our approach has been to combine structural and functional studies to understand how these proteins bind and signal through their receptors, and what molecular features confer receptor specificity. We will focus on the monocyte chemoattractant protein 1 and its receptor CCR2, fractalkine and its receptor CX3CR1, viral chemokine homologues, and human chemokine-viral receptor complexes. The objectives of this proposal are as follows: 1. Continue structure-function studies of MCP-1 and fractalkine to map residues involved in binding, chemotaxis, and activation of specific signaling pathways. 2. Identify residues involved in surface glycosaminoglycan presentation of MCP-1. Investigate the role of chemokine oligomerization on function. 3. Characterize the interaction between chemokines and extracellular domains of their receptors by NMR. 4. Express and characterize novel viral chemokines, and complexes between human chemokines and soluble viral receptors.
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