C4b

C4b is a fragment of the complement protein C4, a component of the classical and lectin pathways of the complement system. It is produced when the initiator enzymes C1s (classical pathway) or MASP-2 (lectin pathway) cleave C4 to yield C4a and C4b. C4b contains a reactive thioester bond that enables covalent attachment to nearby surfaces, such as microbial membranes, after activation.

On pathogen surfaces, C4b binds to the protease C2 to form the C4b2 complex. This complex is then targeted by proteolysis of C2 to generate C2a, producing the C4b2a complex, which acts as the C3 convertase of the classical and lectin pathways. The C3 convertase cleaves C3 into C3a and C3b, amplifying the cascade and promoting opsonization and inflammation. The C3b fragment can also become covalently attached to surfaces and contribute to further steps in the cascade, including the formation of the C5 convertase (C4b2a3b) when additional C3b is deposited.

C4b also functions as an opsonin, marking surfaces for phagocytosis. Its activity is tightly regulated to protect host tissues; regulators such as C4b-binding protein (C4BP) and membrane-bound decay-accelerating factors (like CR1/CD35 and DAF/CD55) help terminate the C4b2a convertase and prevent excessive activation. Factor I, with appropriate cofactors, inactivates C4b by cleaving it to inactive fragments C4c and C4d.

Genetically, humans carry C4A and C4B genes that encode different allotypes; C4b is generated specifically from the C4B gene product. Dysregulation or deficiencies in C4 or its regulatory components can be associated with immune complex diseases and increased susceptibility to infections.