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. 2011 Aug 9;108(32):13236-40.
doi: 10.1073/pnas.1106746108. Epub 2011 Jul 25.

Unique structure of iC3b resolved at a resolution of 24 Å by 3D-electron microscopy

Martin Alcorlo  1 , Ruben Martínez-Barricarte, Francisco J Fernández, César Rodríguez-Gallego, Adam Round, M Cristina Vega, Claire L Harris, Santiago Rodríguez de Cordoba, Oscar Llorca
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"V体育官网" Unique structure of iC3b resolved at a resolution of 24 Å by 3D-electron microscopy

"V体育官网入口" Martin Alcorlo et al. Proc Natl Acad Sci U S A. .

Erratum in

  • Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):16481

V体育平台登录 - 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 VSports手机版. 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. .

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"VSports" Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Purification and EM of iC3b. (A) Final preparations of purified C3, C3b, and iC3b were analyzed by SDS/PAGE. Schematic representation of the primary structure of iC3b is also shown. (B) Reference-free 2D averages of iC3b single-molecule images. Several views of iC3b correspond to a distinct orientation of the protein on the support film. (C) Projections of the EM structure of iC3b obtained by the angular refinement method match the reference-free averages, as shown in B. (D) Selected 2D reference-free average shows a typical view of iC3b. A cartoon highlights the location of the MG ring (blue) and a large density at the top (gray). (E) As in D, but a typical reference-free average of C3 and C3b molecules observed in the electron microscope is shown (6).
Fig. 2.
Fig. 2.
3D structure of iC3b obtained by 3D-EM. (A) 3D structure of iC3b shown as a gray transparent density. The atomic structure of the MG ring (blue) and the C345C domains (orange) were obtained from the structure of C3b (PDB ID code 2I07) (21) and fitted within the EM structure. The putative locations of the TED domain and the remains of the CUB domain in the map have been colored in green and red, respectively. The primary sequence of iC3b chains is also shown. (B) 3D structure of iC3b shown as a gray transparent density, where the MG rings of C3 (PDB ID code 2A73; blue) (20) and C3b (PDB ID code 2I07) (21) have been fitted. The structure of the MG ring in C3 does not fit accurately into the iC3b structure, leaving regions of iC3b unoccupied (labeled as *).
Fig. 3.
Fig. 3.
Global shape of iC3b obtained by SAXS. (A) P(r) functions for C3 (blue), C3b (green), and iC3b (orange) computed from experimental SAXS data. The P(r) function for the EM structure of iC3b (shown in gray) was computed from an equivalent bead model. The P(r) functions are normalized to unity at their maxima. The intersection of each function with the abscissa yields the experimental averaged maximal diameter. P(r), pair distance distribution. (B) Characteristic views of the C3, iC3b, and C3b ab initio models, colored as in A.
Fig. 4.
Fig. 4.
Molecular architecture of iC3b. The atomic structures of C3 (PDB ID code 2A73) (20) and C3b (PDB ID code 2I07) (21) were filtered to a resolution similar to that of the structure of iC3b obtained by EM.
See this image and copyright information in PMC

References

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