The lectin (LP) and classical (CP) pathways are two of the three main activation cascades of the complement system. These pathways start with recognition of different pathogen-or danger-associated molecular patterns and include identical steps of proteolytic activation of complement component C4, formation of the C3 proconvertase C4b2, followed by cleavage of complement component C2 within C4b2 resulting in the C3 convertase C4b2a. Here, we describe the solution structures of the two central complexes of the pathways, C3 proconvertase and C3 convertase, as well as the unbound zymogen C2 obtained by small angle x-ray scattering analysis. We analyzed both native and enzymatically deglycosylated C4b2 and C2 and showed that the resulting structural models were independent of the glycans. The small angle x-ray scattering-derived models suggest a different activation mode for the CP/LP C3 proconvertase as compared with that established for the alternative pathway proconvertase C3bB. This is likely due to the rather different structural and functional properties of the proteases activating the proconvertases. The solution structure of a stabilized form of the active CP/LP C3 convertase C4b2a is strikingly similar to the crystal structure of the alternative pathway C3 convertase C3bBb, which is in accordance with their identical functions in cleaving the complement proteins C3 and C5.The human complement system performs a broad range of roles, including defense against invading pathogens, modulation of adaptive immune system responses, and maintenance of the body's homeostasis (1, 2). The lectin (LP) 3 and classical (CP) pathways are two of the main activation cascades of complement. They are triggered when pattern recognition molecules, C1q in the CP and the collectins/ficolins in the LP, bind to molecular patterns associated with pathogens or altered self (3, 4). Upon binding, the proteases associated with the pattern recognition molecules become active, C1r and C1s in the CP and MBL-associated serine proteases (MASP)-1 and MASP-2 in the LP. C1s and MASP-2 subsequently cleave complement component C4, generating C4b (Fig. 1A) (5). C4b adopts a conformation very different from that of C4 (6) and binds the zymogen C2 in a Mg 2ϩ -dependent manner (7). Together they form the CP/LP C3 proconvertase complex, C4b2. Within this complex, C2 can be cleaved by C1s, MASP-1, and MASP-2 into two fragments as follows: the large C2a, comprising a von Willebrand factor (vWf) domain and a serine protease (SP) domain, and the smaller C2b consisting of three complement control protein (CCP) domains (7-9). C2b dissociates (10) whereas C2a stays bound to C4b, forming the CP/LP C3 convertase C4b2a (11). Two areas in C2 are involved in binding to C4b in the proconvertase. One is located on the CCP1-3 domains (12), and the second is the metal ion-dependent adhesion site (MIDAS) of the vWf domain that coordinates a Mg 2ϩ ion under physiological conditions (13). Within the C3 convertase, the MIDAS interaction is essential for the binding of C2a ...