title: Unique structure of iC3b resolved at a resolution of 24 Å by 3D-electron microscopy.
abstract: Activation of C3, deposition of C3b on the target surface, and subsequent amplification by formation of a C3-cleaving enzyme (C3-convertase; C3bBb) triggers the effector functions of complement that result in inflammation and cell lysis. Concurrently, surface-bound C3b is proteolyzed to iC3b by factor I and appropriate cofactors. iC3b then interacts with the complement receptors (CR) of the Ig superfamily, CR2 (CD21), CR3 (CD11b/CD18), and CR4 (CD11c/CD18) on leukocytes, down-modulating inflammation, enhancing B cell-mediated immunity, and targeting pathogens for clearance by phagocytosis. Using EM and small-angle X-ray scattering, we now present a medium-resolution structure of iC3b (24 Å). iC3b displays a unique conformation with structural features distinct from any other C3 fragment. The macroglobulin ring in iC3b is similar to that in C3b, whereas the TED (thioester-containing domain) domain and the remnants of the CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1) domain have moved to locations more similar to where they were in native C3. A consequence of this large conformational change is the disruption of the factor B binding site, which renders iC3b unable to assemble a C3-convertase. This structural model also justifies the decreased interaction between iC3b and complement regulators and the recognition of iC3b by the CR of the Ig superfamily, CR2, CR3, and CR4. These data further illustrate the extraordinary conformational versatility of C3 to accommodate a great diversity of functional activities.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain.
authors.forename: Martin
authors.initials: M
authors.lastname: Alcorlo
authors.forename: Ruben
authors.initials: R
authors.lastname: Martínez-Barricarte
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Fernández
authors.forename: César
authors.initials: C
authors.lastname: Rodríguez-Gallego
authors.forename: Adam
authors.initials: A
authors.lastname: Round
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Vega
authors.forename: Claire L
authors.initials: CL
authors.lastname: Harris
authors.forename: Santiago Rodríguez
authors.initials: SR
authors.lastname: de Cordoba
authors.forename: Oscar
authors.initials: O
authors.lastname: Llorca
mesh_terms: D003179:Complement C3b / Q000737:chemistry* / Q000302:isolation & purification / Q000648:ultrastructure*; D006801:Humans; D008854:Microscopy, Electron; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D017463:Receptors, Complement 3b / Q000737:chemistry; D053838:Scattering, Small Angle; D012996:Solutions; D014961:X-Ray Diffraction
chemical_list: D017463:Receptors, Complement 3b; D012996:Solutions; D003179:Complement C3b