C-Reactive Protein: Structural Biology and Host Defense Function

Abstract

Human C-reactive protein is a Ca2+-binding acute phase-protein with binding specificity for phosphocholine. Recent crystallographic and mutagenesis studies have provided a solid understanding of the structural biology of the protein, while experiments using transgenic mice have confirmed its host-defense function. The protein consists of five identical protomers in cyclic symmetry. On one face of each protomer there is a binding site for phosphocholine consisting of two Ca2+ ions that ligate the phosphate group and a hydrophobic pocket that accommodates the methyl groups of phosphocholine. On the opposite face is a deep cleft formed by parts of the N and C termini and bordered by an alpha-helix. Mutational studies indicate that the C1q-binding site of the molecule is located at the open end of this cleft with Asp112 and Tyr175 representing contact residues. Using human C-reactive protein transgenic mice, we investigated the host defense functions of the protein. Transgenic mice infected with Streptococcus pneumoniae had increased lifespan and lowered mortality compared to wild-type mice. This was attributable to an up to 400-fold reduction in bacteremia mediated mainly by the interaction of C-reactive protein with complement. A complement-independent host protective effect was also demonstrated.

A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor

“…Both are members of the pentraxin family, with a similar pentagonal arrangement of their subunits and display calcium-dependent binding to specific substrates. 64,65 In addition, both mouse SAP and human CRP respond to IL-1␤ and IL-6 stimulation, which enhances binding of STAT3 and C/EBP␤ to their promoters. In contrast, previous findings indicate that only STAT3 is involved in mouse CRP gene expression rather than a complex, synergistic interaction between STAT3 with C/EBP-␤.…”

Crystal structures for short-chain pentraxin from zebrafish demonstrate a cyclic trimer with new recognition and effector faces

“…Short-chain pentraxins are involved in acute-phase response (APR) and recognise various pathogenic bacteria or cellular debris in a characteristic calcium-dependent manner (Abernethy and Avery, 1941;Thompson et al, 1999). CRP binds primarily to phosphorylcholine (PC) (Narkates and Volanakis, 1982;Szalai et al, 1999), whereas SAP binds to amyloid fibrils and the cyclic 4,6-pyruvate acetal of b-D-galactose (Hind et al, 1984). Currently, CRP and SAP are extensively used as biomarkers of various diseases and are targeted in cardiovascular disease treatment (Pepys et al, 2006).…”

The Crystal Structure of the Globular Head of Complement Protein C1q Provides a Basis for Its Versatile Recognition Properties

“…These include certain bacteria, viruses, parasites, and mycoplasma (6, 10 -12), underscoring its role as an antibody-independent defense protein. C1q also binds to C-reactive protein (CRP) 1 when complexed with exposed phosphocholine residues on bacteria, providing a further means of host defense (13). C1q is also capable of recognizing aberrant structures from self.…”