Identification and characterization of a glycosaminoglycan recognition element of the C chemokine lymphotactin

doi:10.1074/jbc.M311633200

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Papers In Press, published online ahead of print January 5, 2004
J. Biol. Chem, 10.1074/jbc.M311633200
Submitted on October 23, 2003
Revised on January 5, 2004
Accepted on January 5, 2004

Identification and characterization of a glycosaminoglycan recognition element of the C chemokine lymphotactin

Francis C. Peterson, E. Sonay Elgin, Timothy J. Nelson, Fuming Zhang, Theresa J. Hoeger, Robert J. Linhardt, and Brian F. Volkman

Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226

Corresponding Author: bvolkman{at}mcw.edu

Chemokine-mediated recruitment of leukocytes in vivo depends on interactions with cell-surface glycosaminoglycans. Lymphotactin, the unique member of the ‘C’ chemokine subclass, is a highly basic protein that binds heparin, a glycosaminoglycan, with high affinity (~10 nM). We detected lymphotactin-heparin binding by NMR and mapped this interaction to a narrow surface that wraps around the protein. Substitutions in and around this binding site and surface plasmon resonance analysis of heparin binding affinity identified two arginine residues of lymphotactin as critical for glycosaminoglycan binding. Both arginine mutant proteins and the combined double mutant had dramatically diminished in vivo activity in a leukocyte recruitment assay, suggesting that the lymphotactin-glycosaminoglycan interactions detected in vitro are important for the function of this chemokine. Our results demonstrate that like other chemokines, lymphotactin utilizes highly specific glycosaminoglycan-binding sites that represent potential targets for drug development.

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