Complement Control Molecules

COMPLEMENT CONTROL MOLECULES:

Complement has the potential to be deadly to cells of any kind, both foreign and host. For example, if C5b ends up on a host cell, the MAC can be formed and destroy the non-invasive cell – a scenario known as "innocent bystander lysis." It is therefore of crucial importance that the complement cascade be tightly controlled. Numerous molecules can interrupt both the alternative and classical pathways at various points in the cascade. Some of these molecules, particularly those mimicked by invading pathogens, will be described here.

The soluble C4b-binding protein (C4bBP) binds to the C4b fragment and inhibits it from interacting with C2a, thus blocking the formation of the C3 convertase. After C4b is bound, the enzyme Factor I cleaves C4b, rendering it inactive.

Complement receptor type 1 (CR1) and mebrane cofactor protein (MCP) are both cofactors for the cleavage of both C4b and C3b – factors necessary for the formation of the C3 convertase in the classical and alternative pathways, respectively. These two membrane-bound proteins allow Factor I to come in and cleave each of these proteins. In the alternative pathway an additional protein, Factor H, can mediate the cleavage of C3b by Factor I.

Another critical regulator of complement is decay-accelerating factor (DAF). When DAF attaches to the C3 convertase of either pathway, the two attached components of the convertase dissociate from one another which results in loss of convertase activity.

Finally, the human protein, CD59, can inhibit the formation of the MAC by interfering with the deposition of C9 molecules.

These regulatory proteins, and many others not mentioned here are all located in a particular region of the human genome known as the regulators of complement activation (RCA) cluster. Furthermore, each of these proteins contains a similar repeating section of amino acids called the short consensus repeat (SCR). This information is important in the characterization of microbial molecules which mimic some of these host complement regulatory proteins.

COMPLEMENT REGULATORY PROTEIN SUMMARY:

Host Regulatory Protein:	Fragment Specificity:	Selected Roles:
Factor I	C3b or C4b	Protease that inactivates C4b or C3b with the help of cofactors CR1, MCP and factor H
Factor H	C3b	Acts as cofactor in the cleavage of C3b by factor I
C4b-BP	C4b	Acts as cofactor in the cleavage of C4b by factor I
CR1	C3b, C4b	Acts as a cofactor in the cleavage of C3b or C4b by factor I; Mediates phagocytosis of opsonized antigens
MCP	C3b, C4b	Acts as a cofactor in the cleavage of C3b or C4b by factor I
DAF	C4b2a or C3bBb	Accelerates decay of C3/C5 convertases
CD 59	C9	Inhibits MAC formation by interfering with C9

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