The proteins of the classical pathway and their mechanisms of action

CI is a multimeric protein consisting of two molecules each of the serine protease proenzymes Clr and Cls bound to a single molecule of Clq. The associations of Clq, Clr and Cls are the Ca2+ ion-dependent stages of the pathway. Clq itself consists of 18 polypeptide chains, of three different types, A, B and C, which are encoded by separate, closely linked genes on the short arm of human chromosome 1. The A, B and C chains are each about 225 amino acids long, and are homologous to each other. Each consists of a short N-terminal region containing a cysteine residue, followed by a stretch of 81 amino acids of collagenous sequence (i.e. repeating triplets of sequence Gly-X-Y, where Y is often a hydroxylated proline or lysine residue). The rest of the sequence is noncollagenous. The collagenous regions of one A, one B and one C chain align to form a short stretch of collagen triple helix structure, and the rest of the three chains fold to form a globular head, which consists of three lobes, one derived from each of the A, B and C chains (Figure 2). The collagenous stalk is bent in the middle, because of irregularities in the collagenous sequences. Fully assembled Clq (Figure 2) has a single cylindrical core, made up of the N-terminal ends of the six collagen triple helices: at the bend in the middle of the helices, they splay apart, forming six stalks, which join the six globular heads to the core. The overall appearance of Clq is likened to a bunch of six tulips. The globular head regions of CI q are responsible for recognition and binding to most classical pathway activators,

Binding to complement activators

Binding to C1r, C1s and C1q-R

Figure 2 The assembly of C1 q from three types of polypeptide chains. The assembly is discussed in the text. MBL has similar structure and assembly, but only one type of polypeptide chain.

Binding to complement activators

Binding to C1r, C1s and C1q-R

Figure 2 The assembly of C1 q from three types of polypeptide chains. The assembly is discussed in the text. MBL has similar structure and assembly, but only one type of polypeptide chain.

while the collagenous regions interact with the next complement proteins in the pathway, Clr and Cls.

Clr and Cls are serine protease proenzymes, encoded by closely linked genes on human chromosome 12pl3. Each monomer consists of a single polypeptide chain of about 700 amino acids: the C-terminal approximately 250 amino acids in each is a serine protease domain, homologous to trypsin or chymo-trypsin. Like most complement proteins, they are mosaic proteins, i.e. segments of the primary sequence can be recognized as being homologous to segments of many other proteins, and are likely to represent independently folding domains or modules. The approximately 450 N-terminal amino acids of Clr and Cls are homologous to each other, and are made up of five domains (see Figure 3). Each con-

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