Structure and activation of C1, the complex initiating the classical pathway of the complement cascade

Abstract

The complement system is an important antimicrobial and inflammation-generating component of the innate immune system. The classical pathway of complement is activated upon binding of the 774-kDa C1 complex, consisting of the recognition molecule C1q and the tetrameric protease complex C1r 2 s 2 , to a variety of activators presenting specific molecular patterns such as IgG-and IgM-containing immune complexes. A canonical model entails a C1r 2 s 2 with its serine protease domains tightly packed together in the center of C1 and an intricate intramolecular reaction mechanism for activation of C1r and C1s, induced upon C1 binding to the activator. Here, we show that the serine protease domains of C1r and C1s are located at the periphery of the C1r 2 s 2 tetramer both when alone or within the nonactivated C1 complex. Our structural studies indicate that the C1 complex adopts a conformation incompatible with intramolecular activation of C1, suggesting instead that intermolecular proteolytic activation between neighboring C1 complexes bound to a complement activating surface occurs. Our results rationalize how a multitude of structurally unrelated molecular patterns can activate C1 and suggests a conserved mechanism for complement activation through the classical and the related lectin pathway.innate immunity | complement | proteolytic cascade | structural biology

Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement

“…The observed arrangement of the C1r and C1s heterotetramer differs from predictions based on a tetrameric C1s arrangement (25,31). The CUB2 domains of C1r and C1s are rotated, and the C1r-C1s dimers are shifted along each other, shortening the contact sites of C1q-collagen helices 2 and 5 from 14 (31) to 11 nm in C1-IgG1 6 ( fig.…”

“…The arrangement of the C1q arms, induced upon binding the Fc hexamer, is also indicative of a compaction. The gC1q domains in unbound C1 are spread apart up to 30 to 35 nm (31). Bending of the collagen-like helices of arms 3 and 6, which embrace C1r 2 s 2 in the longest dimension, and incomplete binding of the gC1q heads (on arms 5 and 6) to Fc platforms support the notion of a surface-induced conformational change.…”

Reply to Arlaud et al.: Structure of the C1 complex and the unbound C1r 2 s 2 tetramer

“…However, the micrographs presented in that study (10) and a related contemporary study (11) do not prove a central location of the C1r and C1s SP domains. Our SAXS rigid body modeling of the nonactivated C1 complex placed the C1r and C1s SP domains at the periphery independent of their initial position, and this location was supported by our ab initio SAXS modeling (2). Consistently, our ns EM class averages showed up to 10 protruding spherical domains in agreement with six C1q globular heads and four SP domains from C1r and C1s located in the periphery of C1.…”

“…1) fit the SAXS data better (χ 2 = 1.26 ± 0.07) than the models we described in ref. 2. The analysis that we presented in ref.…”

“…A representative output model is now deposited in the Small Angle Scattering Biological Data Bank, together with a model from our study (2).…”