The crystal structure of iC3b-CR3 αI reveals a modular recognition of the main opsonin iC3b by the CR3 integrin receptor

Francisco J. Fernández (), Jorge Santos-López, Rubén Martínez-Barricarte, Javier Querol-García, Héctor Martín-Merinero, Sergio Navas-Yuste, Martin Savko, William E. Shepard, Santiago Rodríguez de Córdoba and M. Cristina Vega ()
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Francisco J. Fernández: Agencia Estatal Consejo Superior de Investigaciones Científicas
Jorge Santos-López: Agencia Estatal Consejo Superior de Investigaciones Científicas
Rubén Martínez-Barricarte: Agencia Estatal Consejo Superior de Investigaciones Científicas
Javier Querol-García: Agencia Estatal Consejo Superior de Investigaciones Científicas
Héctor Martín-Merinero: Agencia Estatal Consejo Superior de Investigaciones Científicas
Sergio Navas-Yuste: Agencia Estatal Consejo Superior de Investigaciones Científicas
Martin Savko: L’Orme des Merisiers Saint-Aubin
William E. Shepard: L’Orme des Merisiers Saint-Aubin
Santiago Rodríguez de Córdoba: Agencia Estatal Consejo Superior de Investigaciones Científicas
M. Cristina Vega: Agencia Estatal Consejo Superior de Investigaciones Científicas

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29580-2

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