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Topology and Structure of the C1q-Binding Site on C-Reactive Protein¹

Alok Agrawal^2,*, Annette K. Shrive, Trevor J. Greenhough and John E. Volanakis^3,*,

^* Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, AL 35294; School of Life Sciences, Keele University, Keele, Staffordshire, United Kingdom; and Biomedical Sciences Research Center "A. Fleming," Vari, Greece

The host defense functions of human C-reactive protein (CRP) depend to a great extent on its ability to activate the classical complement pathway. The aim of this study was to define the topology and structure of the CRP site that binds C1q, the recognition protein of the classical pathway. We have previously reported that residue Asp¹¹² of CRP plays a major role in the formation of the C1q-binding site, while the neighboring Lys¹¹⁴ hinders C1q binding. The three-dimensional structure of CRP shows the presence of a deep, extended cleft in each protomer on the face of the pentamer opposite that containing the phosphocholine-binding sites. Asp¹¹² is part of this marked cleft that is deep at its origin but becomes wider and shallower close to the inner edge of the protomer and the central pore of the pentamer. The shallow end of the pocket is bounded by the 112–114 loop, residues 86–92 (the inner loop), the C terminus of the protomer, and the C terminus of the pentraxin -helix 169–176, particularly Tyr¹⁷⁵. Mutational analysis of residues participating in the formation of this pocket demonstrates that Asp¹¹² and Tyr¹⁷⁵ are important contact residues for C1q binding, that Glu⁸⁸ influences the conformational change in C1q necessary for complement activation, and that Asn¹⁵⁸ and His³⁸ probably contribute to the correct geometry of the binding site. Thus, it appears that the pocket at the open end of the cleft is the C1q-binding site of CRP.

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