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Rational design of a novel calcium-binding site adjacent to the ligand-binding site on CD2 increases its CD48 affinity

¹ Department of Chemistry, Center for Drug Design and Biotechnology, Georgia State University, Atlanta, Georgia 30303, USA
² Sir William Dunn School of Pathology, University of Oxford, Oxford OXI 3RE, United Kingdom

(RECEIVED November 1, 2007; FINAL REVISION December 4, 2007; ACCEPTED December 7, 2007)

Electrostatic interactions are important for molecular recognition processes including Ca²⁺-binding and cell adhesion. To understand these processes, we have successfully introduced a novel Ca²⁺-binding site into the non-Ca²⁺-dependent cell adhesion protein CD2 using our criteria that are specifically tailored to the structural and functional properties of the protein environment and charged adhesion surface. This designed site with ligand residues exclusively from the β-sheets selectively binds to Ca²⁺ and Ln³⁺ over other mono- and divalent cations. While Ca²⁺ and Ln³⁺ binding specifically alters the local environment of the designed Ca²⁺-binding site, the designed protein undergoes a significantly smaller conformation change compared with those observed in naturally occurring Ca²⁺-binding sites that are composed of at least part of the flexible loop and helical regions. In addition, the CD2–CD48-binding affinity increased approximately threefold after protein engineering, suggesting that the cell adhesion of CD2 can be modulated by altering the local electrostatic environment. The study provides site-specific information for regulating cell adhesion within CD2 and gives insight into the structural factors required for Ca²⁺-modulated biological processes.

Keywords: calcium-binding sites; cell adhesion; metal-binding affinity; metal selectivity; rational design

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