The crystal structure of iC3b-CR3 αI reveals a modular recognition of the main opsonin iC3b by the CR3 integrin receptor
16 p.-9 fig. ; Complement activation on cell surfaces leads to the massive deposition of C3b, iC3b, and C3dg, the main complement opsonins. Recognition of iC3b by complement receptor type 3 (CR3) fosters pathogen opsonophagocytosis by macrophages and the stimulation of adaptive immunity by complement-opsonized antigens. Here, we present the crystallographic structure of the complex between human iC3b and the von Willebrand A inserted domain of the α chain of CR3 (αI). The crystal contains two composite interfaces for CR3 αI, encompassing distinct sets of contiguous macroglobulin (MG) domains on the C3c moiety, MG1-MG2 and MG6-MG7 domains. These composite binding sites define two iC3b-CR3 αI complexes characterized by specific rearrangements of the two semi-independent modules, C3c moiety and TED domain. Furthermore, we show the structure of iC3b in a physiologically-relevant extended conformation. Based on previously available data and novel insights reported herein, we propose an integrative model that reconciles conflicting facts about iC3b structure and function and explains the molecular basis for iC3b selective recognition by CR3 on opsonized surfaces. ; This work was funded by Spanish Ministerio de Ciencia, Innovación y Universidades-FEDER grant RTI2018-102242-B-I00 (to M.C.V.) and PID2019-104912RB-I00 (to S.R.C.), and Spanish Ministerio de Economía y Competitividad-FEDER grants SAF2015-72961-EXP (to M.C.V.) and SAF2015-66287-R (to S.R.C.). It was also funded by Grant S2017/BMD-3673 of the Regional Government of Madrid and the European Commission – NextGenerationEU through CSIC's Global Health Platform ("PTI Salud Global") (SGL2103020) (to S.R.C. and M.C.V.), and the CSIC Special Intramural Grant PIE-201620E064 (to M.C.V.). It was additionally supported by the Network of Excellence Complement in Health and Disease (SAF2016-81876-REDT). SRC was also supported by the CIBER de Enfermedades Raras. JSL acknowledges the support of the PhD program in Molecular Biosciences of the Universidad Autónoma de Madrid (UAM) and the Ministry of Education, Culture and Sports of Spain (FPU Grant 17/06090). SNY acknowledges the support of the PhD program in Biochemistry, Molecular Biology and Biomedicine of the Universidad Complutense de Madrid (UCM). ; Peer reviewed