Sci. Signal., 8 April 2008
Structural Biology Shape-Shifting Chemokines
Science Signaling, AAAS, Washington, DC 20005, USA
Lymphotactin (Ltn) is the odd-man-out amongst the chemokines. Whereas all the others have two disulfide bridges, Ltn has only one, a distinctive feature that may explain its unique structural properties. In vitro Ltn adopts two conformations: Ltn10, which predominates in high-salt conditions at low temperatures (10°C), and Ltn40, a high-temperature, low-salt (40°C) form. The two forms are in equilibrium under physiological conditions. Tuinstra et al. addressed the functional implications of this conformational variability. Nuclear magnetic resonance studies showed that Ltn10 and Ltn40 corresponded to distinct structures that used different combinations of amino acid residues for internal hydrogen bonding. The authors engineered recombinant Ltn10 and Ltn40 proteins by making amino acid substitutions that trapped the protein in one conformation or the other. Like other chemokines, Ltn binds to both its receptor (XCR1) and extracellular matrix glycosaminoglycans such as heparin. However, recombinant Ltn10 bound with high affinity to XCR1, but not to heparin, whereas recombinant Ltn40 bound with high affinity to heparin, but not XCR1. Neither protein mimicked the activity of Ltn in stimulating chemotaxis of human T cells in vitro. Furthermore, the authors found that Ltn could not bind to XCR1 and heparin simultaneously and suggested that Ltn must release the extracellular matrix component before it binds to and activates its receptor. This study suggests that altering the equilibrium between two conformational states of a protein by changing physiological conditions such as temperature (for example, during inflammation) may constitute a previously unrecognized means of affecting signaling pathway dynamics.
R. L. Tuinstra, F. C. Peterson, S. Kutlesa, E. S. Elgin, M. A. Kron, B. F. Volkman, Interconversion between two unrelated protein folds in the lymphotactin native state. Proc. Natl. Acad. Sci. U.S.A. 105, 5057-5062 (2008). [Abstract] [Full Text]
Citation: A. VanHook, Shape-Shifting Chemokines. Sci. Signal. 1, ec122 (2008).
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