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Binding complement with complementarity
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Research Themes Immunology

Binding complement with complementarity

SBKB [doi:10.1038/sbkb.2011.22]
Featured Article - June 2011
Short description: The structure of complement C3d with complement receptor 2 answers lingering questions about the interaction of these two proteins.

Top: a schematic illustrating how antigen-C3d acts as a bridge between the B cell antigen receptor (BCR) and the CR2/CD19/CD81 coreceptor complex. Bottom: the interaction surface between C3d and CR2, formed by shape complementarity. Image from David Isenman and Jean van den Elsen. [PDB: 3OED]

Found on B cells and follicular dendritic cells, complement receptor 2 (CR2) binds the degradation products of complement C3 (iC3b, C3b, C3dg or C3d), where these C3 fragments have covalently “tagged” an antigenic surface. At the same time, CR2 is associated with CD19 and CD81 on B cells, and this co-receptor complex leads to a sensitizing of B cells to antigens. Therefore, understanding the interaction between CR2 and C3d is of great importance for potentially modulating this interface between adaptive and innate immunity.

An X-ray crystal structure of C3d bound to the CR2 SCR domains (CR2(SCR1-2)) had been determined previously; however, the interactions seen in that structure conflict with the results of several studies that used biochemical approaches to look at the same complex. As a result, there has until now been no clear picture of how these two proteins interact. As a detailed characterization of this complex is of interest to researchers examining both autoimmune diseases and the regulation of adaptive immunity, van den Elsen and Isenman now report in Science a new crystal structure of the C3d–CR2(SCR1-2) complex at 3.16-Å resolution.

In the structure, the interaction interface between C3d and CR2(SCR1-2) has a buried surface area of 2,250 Å2 and is formed through shape complementarity as the V-shaped SCR domains interact with the acidic pocket located on the concave surface of C3d. C3d interacts primarily with SCR1, with the C3d–SCR2 interface contributing a substantially smaller amount of buried surface area. As would be expected for interactions involving an acidic surface, binding is mediated extensively by salt bridges and hydrogen bonds. Interestingly, none of the interactions reported by the previous structure was seen in this new crystal.

Given the discrepancies between the two structures, it is important to consider both in light of other available data. The new interface is corroborated by previously published biochemical data as well as new mutational analysis carried out by the authors, with Lys108 and Arg83 of SCR2 being seen to make important contributions to the interaction between the two proteins. Additionally, the new structure provides a mechanistic explanation for how other SCR1 and SCR2 residues implicated by mutagenesis contribute to binding.

The insights gleaned from this structure of the C3d–CR2(SCR1-2) complex will allow researchers to target this interaction with small molecules or antibodies. As a result, future scientists will hopefully be able to either up- or downregulate B-cell reactivity as desired through modulation of this linkage point between the complement pathways and the adaptive immune system.

Steve Mason


  1. J.M.H. van den Elsen & D.E. Isenman A crystal structure of the complex between human complement receptor 2 and its ligand C3d.
    Science 332, 608-611 (2011). doi:10.1126/science.1201954

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