Complement regulatory proteins

Protein	Location	Function	Comment	Disease*
C1 inhibitor	Plasma	Inactivates C1 and MASPs	Binds C1r/C1s, MASPs	HAE
C4BP^¶	Plasma	DAA and CA	Binds C4b	One case of aHUS
Factor H (FH)	Plasma	DAA and CA	Binds C3b	aHUS, AMD, C3G
DAF (CD55)	Membrane	DAA	Prevents formation of and dissociates C3/C5 convertases	CHAPLE syndrome; PNH^Δ
MCP (CD46)	Membrane	CA	Binds C3b and C4b to all factor I-mediated cleavage	Primarily aHUS, but also pregnancy-related disorders and CVID
CR1 (CD35)	Membrane	DAA and CA	Binds C3b, C4b, C1q, and MBL	–
CRIg	Membrane	Blocks alternative pathway	Binds C3b and iC3b	–
CSDM1	Membrane	CA	Binds C3b	–
Factor I (FI)	Plasma	Protease that cleaves C3b and C4b	Requires a cofactor, such as MCP or factor H	aHUS, AMD
Anaphylatoxin inactivator (carboxypeptidase N)	Plasma	Protease that inactivates anaphylatoxins	Binds and cleaves C3a, C4a, and C5a	Some combination of angioedema, chronic urticaria, or hay fever/allergy
Vitronectin	Plasma	Blocks fluid-phase MAC	Binds C5b67	–
CD59	Membrane	Blocks MAC on host cells	Binds C8, C9	PNH^Δ; rare deficiency resulted in Coombs-negative hemolysis and relapsing inflammatory demyelinating polyneuropathy
Clusterin	Plasma	Putative MAC inhibitor	Binds C7, C8, C9	–

MASPs: mannose-binding lectin (MBL)-associated serine proteases; HAE: hereditary angioedema; C4BP: C4b binding protein; DAA: decay-accelerating activity; CA: cofactor activity; aHUS: atypical hemolytic uremic syndrome; AMD: age-related macular degeneration; C3G: C3 glomerulopathy; DAF: decay-accelerating factor or CD55; CHAPLE: complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy; PNH: paroxysmal nocturnal hemoglobinuria; MCP: membrane cofactor protein or CD46; CVID: common variable immunodeficiency; CR1: complement receptor 1 or CD35; MBL: mannose-binding lectin; CRIg: complement receptor of the immunoglobulin superfamily; CSDM1: CUB and sushi multiple domains protein 1; MAC: membrane attack complex.
* Most diseases result from rare heterozygous deficiencies although there are a few cases of homozygous deficiencies. Specifically, there are about 25 cases each of complete C3, FH or FI deficiency. As in C3 deficiency (secondary C3 deficiency occurs with either FH or FI total deficiency), the clinical presentation is that of recurrent bacterial infections, primarily with Streptococcus pneumoniae. Refer to UpToDate content on inherited disorders of the complement system and acquired deficiencies of the complement system for details.
¶ C4BP and factor H transfer from the plasma to damaged cells and exposed acellular tissue surfaces (basement membranes) to prevent undesirable complement activation. This is particularly important in cases of extracellular debris accumulation, as in AMD.
Δ In PNH, both DAF and CD59 are lacking due to a defect in the glycolipid anchoring mechanism.

Graphic 71885 Version 8.0

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Complement regulatory proteins