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

Abstract

Abstract 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 α-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.

Keywords

Affiliated Institutions

• Keele University GB
• Alexander Fleming Biomedical Sciences Research Center GR
• University of Alabama at Birmingham US

Related Publications