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Structural Evidence for the Tetrameric Assembly of Chemokine CCL11 and the Glycosaminoglycan Arixtra™
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, 521 Parnassus Avenue, San Francisco, CA 94143, USA
Perspectives, Inc., 2231 Garden Highway, Sacramento, CA 95833, USA
Department of Molecular and Cellular Biology, University of California, 1 Shields Avenue, Davis, CA 95616, USA
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 22 August 2013; in revised form: 23 October 2013 / Accepted: 29 October 2013 / Published: 6 November 2013
Abstract: Understanding chemokine interactions with glycosaminoglycans (GAG) is critical as these interactions have been linked to a number of inflammatory medical conditions, such as arthritis and asthma. To better characterize in vivo protein function, comprehensive knowledge of multimeric species, formed by chemokines under native conditions, is necessary. Herein is the first report of a tetrameric assembly of the human chemokine CCL11, which was shown bound to the GAG Arixtra™. Isothermal titration calorimetry data indicated that CCL11 interacts with Arixtra, and ion mobility mass spectrometry (IM-MS) was used to identify ions corresponding to the CCL11 tetrameric species bound to Arixtra. Collisional cross sections (CCS) of the CCL11 tetramer-Arixtra noncovalent complex were compared to theoretical CCS values calculated using a preliminary structure of the complex deduced using X-ray crystallography. Experimental CCS values were in agreement with theoretical values, strengthening the IM-MS evidence for the formation of the noncovalent complex. Tandem mass spectrometry data of the complex indicated that the tetramer-GAG complex dissociates into a monomer and a trimer-GAG species, suggesting that two CC-like dimers are bridged by Arixtra. As development of chemokine inhibitors is of utmost importance to treatment of medical inflammatory conditions, these results provide vital insights into chemokine-GAG interactions.
Keywords: CCL11; ion mobility mass spectrometry; chemokine; glycosaminoglycan
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Dykstra, A.B.; Sweeney, M.D.; Leary, J.A. Structural Evidence for the Tetrameric Assembly of Chemokine CCL11 and the Glycosaminoglycan Arixtra™. Biomolecules 2013, 3, 905-922.
Dykstra AB, Sweeney MD, Leary JA. Structural Evidence for the Tetrameric Assembly of Chemokine CCL11 and the Glycosaminoglycan Arixtra™. Biomolecules. 2013; 3(4):905-922.
Dykstra, Andrew B.; Sweeney, Matt D.; Leary, Julie A. 2013. "Structural Evidence for the Tetrameric Assembly of Chemokine CCL11 and the Glycosaminoglycan Arixtra™." Biomolecules 3, no. 4: 905-922.