Structural insight on the recognition of surface-bound opsonins by the integrin I domain of complement receptor 3

Abstract

Complement receptors (CRs), expressed notably on myeloid and lymphoid cells, play an essential function in the elimination of complement-opsonized pathogens and apoptotic/necrotic cells. In addition, these receptors are crucial for the cross-talk between the innate and adaptive branches of the immune system. CR3 (also known as Mac-1, integrin α M β 2 , or CD11b/CD18) is expressed on all macrophages and recognizes iC3b on complement-opsonized objects, enabling their phagocytosis. We demonstrate that the C3d moiety of iC3b harbors the binding site for the CR3 αI domain, and our structure of the C3d:αI domain complex rationalizes the CR3 selectivity for iC3b. Based on extensive structural analysis, we suggest that the choice between a ligand glutamate or aspartate for coordination of a receptor metal ion-dependent adhesion site-bound metal ion is governed by the secondary structure of the ligand. Comparison of our structure to the CR2:C3d complex and the in vitro formation of a stable CR3:C3d: CR2 complex suggests a molecular mechanism for the hand-over of CR3-bound immune complexes from macrophages to CR2-presenting cells in lymph nodes.innate immunity | phagocytosis | integrin receptor | structural biology

Complement C3dg-mediated erythrophagocytosis: implications for paroxysmal nocturnal hemoglobinuria

“…We also identified an anti-C3d mAb that impaired binding of CR3-a M I considerably ( Figure 1F). Although avidity during cell-cell interactions may influence the binding profile, and additional contacts with CR3 may be involved in the case of iC3b, 8 our study demonstrates that C3dg can act as independent binding partner for CR3.…”

“…7 Recently, structural studies revealed that the C3d domain contains the interaction site of iC3b for CR3. 8 We therefore hypothesized that C3dg may act as independent opsonin that contributes to erythrophagocytosis, thereby corroborating the mechanism of extravascular hemolysis in PNH.…”

“…The interaction was Mg 21 dependent ( Figure 1D), supporting reports that CR3 binds the C3d domain via its metal-ion-dependent adhesion site domain. 8 A monoclonal antibody (mAb) known to bind the a M I domain 14 completely blocked the interaction ( Figure 1E) and was used to determine receptor specificity in subsequent experiments. We also identified an anti-C3d mAb that impaired binding of CR3-a M I considerably ( Figure 1F).…”

Production of complement components by cells of the immune system

“…CR1 (CD35) is both a complement receptor for C3b, iC3b and C4b and a complement inhibitor, by competing with factor B (FB) for C3b binding and by functioning as a co-factor for factor I (FI) [6]. CR2 (CD21) binds iC3b, and especially C3d/C3dg, CR3 (MAC-1, CD11b/CD18) binds iC3b and C3d/C3dg, whereas CR4 (gp150/95, CD11c/CD18) binds only iC3b [7][8][9][10][11][12]. Another complement receptor, complement receptor of the immunoglobulin superfamily (CRIg), binds to C3b and iC3b and also to soluble C3c [13,14].…”

Smart Drug Delivery Strategies Based on Porous Nanostructure Materials

“…In the case of ultrasound responsive systems, it is required for the stabilization of acoustic cavitation's gas-liquid interface and the compatibility with liquid interface to generate gas bubbles. The primary requirements of the stabilized system are extended circulation lifetime, effective size range, and efficient stimulated release of encapsulated drug via the application of ultrasound [67][68].…”