Functional role

Host cells must be protected from inadvertent complement activation at sites of inflammation and from the continuous, natural 'tickover' of C3. A biochemical mechanism to regulate C3b/C4b is termed 'cofactor' activity. In this process, CD46 interacts with C3b or C4b to promote their limited enzymatic cleavage by factor I, a plasma serine protease. CD46 possesses 'intrinsic' cofactor activity, i.e. it protects the cell on which it is anchored, not bystander cells.

The reason for the expression of four isoforms in a given cell or tissue is only partially understood. For example, the cytoplasmic tails of CD46 mediate the differential processing of CD46 precursors. Isoforms bearing tail 1 (CYT-1) processed into their mature forms four times faster than isoforms with tail 2 (CYT-2). Additionally, the BC isoforms provide enhanced cytoprotection against the classical pathway as compared to C isoforms. The presence of distinct consensus phosphorylation signals on the cytoplasmic tails suggests roles in cell signaling.

The CCPRs are the sites of functional activity for CD46 and other RCA proteins. C4b-binding and cofactor activity map to CCPRs 2, 3 and 4. To regulate C3b, the third and fourth CCPRs are necessary for binding while 2, 3 and 4 are needed for co-factor activity.

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