Comparative analyses of pentraxins: implications for protomer assembly and ligand binding

Abstract

Background: Pentraxins are a family of plasma proteins characterized by their pentameric assembly and calciumdependent ligand binding. The recent determination of the crystal structure for a member of this family, human serum amyloid P component (SAP), provides a basis for the comparative analysis of the pentraxin family. Results: We have compared the sequences, tertiary structures and quaternary arrangements of SAP with human C-reactive protein (CRP), Syrian hamster SAP (HSAP) and Limulus polyphemus CRP (LIM). These proteins can adopt a 3 -jelly roll topology and a hydrophobic core similar to that seen in SAP. Only minor differences are observed in the positions of residues involved in coordinating calcium ions. Conclusions: Calcium-mediated ligand binding by CRP, HSAP and LIM is similar to that defined by the crystal structure of SAP, but sequence differences in the hydrophobic pocket explain the differential ligand specificities exhibited by the homologous proteins. Differences elsewhere, including insertions and deletions, account for the different (hexameric) quaternary structure of LIM.

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

“…3A and Table 1), a small rmsd (0.265 Å) was generated by superposition. The 11.3 Å shift in the Dare-PTX-Ca K-M loop suggests its role in calcium binding, and it is also observed in the hCRP, hSAP and lSAPl structures (Shrive et al, 2009;Srinivasan et al, 1994;Thompson et al, 1999). After a more detailed analysis in Dare-PTX-Ca, we found that Asp141 in the K-M loop has a 5.2 Å drift and an entirely different flexibility (Fig.…”

Transgenic mice expressing rabbit C-reactive protein are resistant to endotoxemia

“…Our calculations are based on a maximal CRP response that, if anything, underestimates the actual level of lyso-PAF excess. We also do not know whether PAF and lyso-PAF actually compete for the same binding site on CRP in vivo, although it is likely that the PC moiety in each case binds to the single PC binding site on each CRP subunit (30). Similarly, we do not know whether the half-lives of PAF and lyso-PAF are identical in our animals.…”

“…Of those animals expressing CRP, 78% (15͞18) survived the PAF challenge in the presence of lyso-PAF compared with 33% (6͞18) of littermates that were not expressing CRP at the time of lyso-PAF plus PAF administration. Assuming that both lyso-PAF and PAF bind CRP through their PC moieties at the known single PC binding site on CRP (30), this result implies that the protective effect seen in the CRP-expressing animals was not due to sequestration of PAF by PC binding to CRP. Assuming a maximal CRP response in these animals of 200 g͞ml and a 1 ml serum volume, we calculated the concentration of PC binding sites on CRP to be 8 M and the circulating concentration of lyso-PAF to be 9.3 M. Thus, the concentration of lyso-PAF was likely to be in excess of that of CRP and above the K i .…”

The Phosphocholine-binding Pocket on C-reactive Protein Is Necessary for Initial Protection of Mice against Pneumococcal Infection

“…Previous mutational analysis of Thr 76 in CRP has confirmed the significance of the hydrophobic pocket for PCh binding (17). In SAP, at the position corresponding to Thr 76 in CRP, it is a Tyr (Tyr 74 ) (18,19). Pneumococci remain the most common cause of community-acquired pneumonia world-wide (20 -22).…”