C4b is derived from native C4 upon cleavage and release of C4a. It is prepared by cleavage of purified C4 with the classical pathway activated protease C1s enzyme (#A104). Native human C4b is a glycosylated (~7.3%) polypeptide containing three disulfide-linked chains. C4b is central to the function of two of the three pathways of complement (Law, S.K.A. and Reid, K.B.M. (1995)). Both the classical and lectin pathways of complement activation generate surface-bound active proteases that cleave C4 (C1s in the classical pathway and MASP1/2 in the lectin pathway). These enzymes cleave a peptide bond in C4 releasing the anaphylatoxin C4a and activating C4b. For a fraction of a second after proteolytic activation C4b can covalently attach to the surface of the target. The thioester of metastable C4b is highly reactive and is capable of reacting with and covalently coupling C4b to amino or hydroxyl groups on the target surface. There are two variants of C4 that are common in man (C4A and C4B). Animals with only one type generally have C4B. The favored sites of attachment for variants C4A and C4B differ. Metastable C4b produced from C4A attaches primarily to amino groups while C4b produced from the C4B variant binds well to hydroxyl groups as well as amino groups (Law, S.K.A. and Dodds, A.W. (1997)). Surface-bound C4b forms the basis for formation of the C3/C5 convertase enzyme complex C4b,C2a. This enzyme activates C3, deposits C3b and thus converts itself from a weak C5 convertase to a highly efficient C5 convertase with a Km for C5 3000-fold lower than that of the C4b,C2a enzyme alone (Rawal N. and Pangburn M.K. (2003)). Surface-bound C4b is a weak opsonin and is recognized by receptors (CR1) on erythrocytes, lymphoid, and phagocytic cells. All of the complement activating functions of C4b are lost upon cleavage of the alpha chain generating C4c and C4d. The protease factor I cleaves C4b only when C4b is bound with one of the factor I cofactors: C4b binding protein (C4bBP), membrane cofactor protein (MCP) or complement receptor 1 (CR1).
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