Functional model of subcomponent C1 of human complement

Abstract

The domain organization of the zymogen subunits of the first component of human complement † † The nomenclature of complement is that recommended by the World Health Organization (1968); activated components are indicated by a bar, e.g. CIs. Cls, Clr 2 and the complex Cls-Clr 2-Cls was studied by electron microscopy. In the absence of Ca 2+, monomeric Cls was visualized as a dumb-bell-shaped molecule consisting of two globular domains (center-to-center distance 11 nm) connected by a rod. One of the globular domains is assigned to the light chain (B-chain) of the activated molecule, which is homologous to trypsin and other serine proteases. The second globular domain and the rod are assigned to the heavy chain (A-chain) of C 1 ̄ s. The subunit Clr is a stable dimer in the presence or absence of Ca 2+. This dimer Clr 2 was visualized as composed of two dumb-bells of dimensions similar to those observed for Cls. These are connected near the junctions between the rod and one of the globular domains. This leads to the structure of an asymmetrical X with two inner closely spaced globules (center-to-center distance 7 nm) and two outer globules at a larger distance (14 nm). By comparison with fragment ClrII 2, in which part of the A-chain is removed, the inner globular domains were assigned to the catalytic B-chains. This characteristic structure of Clr 2 is readily recognized in the central portion of the thread-like 54 nm long Cls-Clr 2-Cls complex formed in the presence of Ca 2+. By affinity-labeling of Cls with biotin and visualization of avidin-ferritin conjugates in the reconstituted complex, it was demonstrated that Cls forms the outer portion of the complex. A detailed model of Cls-Clr 2-Cls is proposed, according to which two Cls monomers bind to the outer globes of Clr 2 by contacts between their heavy chains and those of Clr. According to this model the catalytic domains of Clr are located in the center and those of Cls at the very tips of the Cls-Clr 2-Cls complex. On the basis of the structure of Cls-Clr 2-Cls, we derived a detailed model of the C1 complex (composed of C1q and the tetrameric complex) and we discuss this model with a view to finding a possible activation mechanism of C1. By analogy with mechanisms proposed for the activation of trypsinogen and plasminogen, we propose that activation of Clr 2 in C1 may be mediated by interaction of the Cls light chain with the Clr light chain domain, thus inducing enzymatic activity in the Clr zymogen, which in turn may lead to a cleavage and final activation of the closely adjacent catalytic domain in the Clr 2 dimer.