Stringent regulation of complement lectin pathway C3/C5 convertase by C4b-binding protein (C4BP).
The complement lectin pathway, an essential component of the innate immune system, is geared for rapid recognition of infections as each C4b deposited via this pathway is capable of forming a C3/C5 convertase. In the present study, role of C4b-binding protein (C4BP) in regulating the lectin pathway C3/C5 convertase assembled on zymosan and sheep erythrocytes coated with mannan (E(Man)) was examined. While the C4BP concentration for inhibiting 50% (IC(50)) formation of surface-bound C3 convertase on the two surfaces was similar to that obtained for the soluble C3 convertase (1.05nM), approximately 3- and 41-fold more was required to inhibit assembly of the C5 convertase on zymosan (2.81nM) and E(Man) (42.66nM). No difference in binding interactions between C4BP and surface-bound C4b alone or in complex with C3b was observed. Increasing the C4b density on zymosan (14,000-431,000 C4b/Zym) increased the number of C4b bound per C4BP from 2.87 to 8.23 indicating that at high C4b density all seven alpha-chains of C4BP are engaged in C4b-binding. In contrast, the number of C4b bound per C4BP remained constant (3.79+/-0.60) when the C4b density on E(Man) was increased. The data also show that C4BP regulates assembly and decay of the lectin pathway C3/C5 convertase more stringently than the classical pathway C3/C5 convertase because of a approximately 7- to 13-fold greater affinity for C4b deposited via the lectin pathway than the classical pathway. C4BP thus regulates efficiently the four times greater potential of the lectin pathway than the classical pathway in generating the C3/C5 convertase and hence production of pro-inflammatory products, which are required to fight infections but occasionally cause pathological inflammatory reactions.
Rawal
Nenoo
N
Department of Biochemistry, University of Texas Health Science Center, 11937, US Highway 271, Tyler, TX 75708, USA. nenoo.rawal@uthct.edu
Rajagopalan
Rema
R
Salvi
Veena P
VP
D000818:Animals; D002645:Chickens; D050577:Complement C3-C5 Convertases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D050716:Complement C4b-Binding Protein / Q000378:metabolism* / Q000494:pharmacology; D004912:Erythrocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008351:Mannans / Q000276:immunology; D012756:Sheep; D015054:Zymosan / Q000276:immunology
D050716:Complement C4b-Binding Protein; D008351:Mannans; D015054:Zymosan; D050577:Complement C3-C5 Convertases