C1

complex

|gG CN^ antibody

Cell surface

FIGURE 12-10 Structure of C1. C1q consists of six identical subunits arranged to form a central core and symmetrically projecting radial arms. The globular heads at the end of each arm, designated H, are the contact regions for immunoglobulin. C1r and C1s form a tetramer composed of two C1r and two C1s molecules. The ends of C1r and C1s contain the catalytic domains of these proteins. One C1r2s2 tetramer wraps around the radial arms of the C1q complex in a manner that juxtaposes the catalytic domains of C1r and C1s.

multiple IgG antibodies are brought together only when they bind to a multivalent antigen. Even though free (circulating) IgM is pentameric, it does not bind C1q because the Fc regions of free IgM are in a planar configuration that is inaccessible to C1q. Binding of the IgM to an antigen induces a conformational change into a "staple" form that exposes the C1q binding sites in the Fc regions and allows C1q to bind. Because of its penta-meric structure, a single molecule of IgM can bind two C1q molecules, and this is one reason that IgM is a more efficient complement-binding (also called complement-fixing) antibody than IgG is.

C1r and C1s are serine proteases that form a tetramer containing two molecules of each protein. Binding of two or more of the globular heads of C1q to the Fc regions of IgG or IgM leads to enzymatic activation of the associated C1r, which cleaves and activates C1s (see Fig. 12-9). Activated C1s cleaves the next protein in the cascade, C4, to generate C4b. (The smaller C4a fragment is released and has biologic activities that are described later.) C4 is homologous to C3, and C4b contains an internal thioes-ter bond, similar to that in C3b, that forms covalent amide or ester linkages with the antigen-antibody complex or with the adjacent surface of a cell to which the antibody is bound. This attachment of C4b ensures that classical pathway activation proceeds on a cell surface or immune complex. The next complement protein, C2, then complexes with the cell surface-bound C4b and is cleaved by a nearby C1s molecule to generate a soluble C2b fragment of unknown importance and a larger C2a fragment that remains physically associated with C4b on the cell surface. (Note that the nomenclature of C2 fragments that is now accepted is different from the other complement proteins because the attached fragment is called the a piece and the released part is the b fragment. This is because, for C2, the attached fragment

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