Match!

Substrate recognition by complement convertases revealed in the C5–cobra venom factor complex

Published on Feb 2, 2011in The EMBO Journal11.227
· DOI :10.1038/emboj.2010.341
N.S. Laursen6
Estimated H-index: 6
(AU: Aarhus University),
Kasper R. Andersen15
Estimated H-index: 15
(AU: Aarhus University)
+ 3 AuthorsGregers R. Andersen36
Estimated H-index: 36
(AU: Aarhus University)
Abstract
Complement acts as a danger-sensing system in the innate immune system, and its activation initiates a strong inflammatory response and cleavage of the proteins C3 and C5 by proteolytic enzymes, the convertases. These contain a non-catalytic substrate contacting subunit (C3b or C4b) in complex with a protease subunit (Bb or C2a). We determined the crystal structures of the C3b homologue cobra venom factor (CVF) in complex with C5, and in complex with C5 and the inhibitor SSL7 at 4.3 A resolution. The structures reveal a parallel two-point attachment between C5 and CVF, where the presence of SSL7 only slightly affects the C5–CVF interface, explaining the IgA dependence for SSL7-mediated inhibition of C5 cleavage. CVF functions as a relatively rigid binding scaffold inducing a conformational change in C5, which positions its cleavage site in proximity to the serine protease Bb. A general model for substrate recognition by the convertases is presented based on the C5–CVF and C3b–Bb–SCIN structures. Prior knowledge concerning interactions between the endogenous convertases and their substrates is rationalized by this model.
  • References (50)
  • Citations (55)
📖 Papers frequently viewed together
146 Citations
201041.04Science
7 Authors (Federico Forneris, ..., Piet Gros)
156 Citations
1,797 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References50
Newest
#1Carl-Wilhelm Vogel (U.H.: University of Hawaii at Manoa)H-Index: 35
#2David C. Fritzinger (U.H.: University of Hawaii at Manoa)H-Index: 13
Cobra venom factor (CVF) is the complement-activating protein in cobra venom. This manuscript reviews the structure and function of CVF, how it interacts with the complement system, the structural and functional homology to complement component C3, and the use of CVF as an experimental tool to decomplement laboratory animals to study the functions of complement in host defense and immune response as well as in the pathogenesis of diseases. This manuscript also reviews the recent progress in usin...
83 CitationsSource
Dense deposit disease (DDD) is a severe renal disease characterized by accumulation of electron-dense material in the mesangium and glomerular basement membrane. Previously, DDD has been associated with deficiency of factor H (fH), a plasma regulator of the alternative pathway (AP) of complement activation, and studies in animal models have linked pathogenesis to the massive complement factor 3 (C3) activation caused by this deficiency. Here, we identified a unique DDD pedigree that associates d...
150 CitationsSource
#1Jovanka Bestebroer (UU: Utrecht University)H-Index: 14
#2Piet C. Aerts (UU: Utrecht University)H-Index: 15
Last. Carla J. C. de Haas (UU: Utrecht University)H-Index: 25
view all 7 authors...
Summary The human pathogen Staphylococcus aureus has a plethora of virulence factors that promote its colonization and survival in the host. Among such immune modulators are staphylococcal superantigen-like (SSL) proteins, comprising a family of 14 small, secreted molecules that seem to interfere with the host innate immune system. SSL7 has been described to bind immunoglobulin A (IgA) and complement C5, thereby inhibiting IgA-FcαRI binding and serum killing of Escherichia coli. As C5a generatio...
67 CitationsSource
#1Georgia Sfyroera (UPenn: University of Pennsylvania)H-Index: 25
#2Daniel Ricklin (UPenn: University of Pennsylvania)H-Index: 39
Last. John D. Lambris (UPenn: University of Pennsylvania)H-Index: 95
view all 8 authors...
3 CitationsSource
#1Michael A. Hadders (UU: Utrecht University)H-Index: 11
#2Michael K. Pangburn (UU: Utrecht University)H-Index: 1
Last. Piet Gros (UU: Utrecht University)H-Index: 47
view all 4 authors...
1 CitationsSource
#1Brian E. Hew (U.H.: University of Hawaii at Manoa)H-Index: 3
#2Katina Wong (U.H.: University of Hawaii at Manoa)H-Index: 2
Last. David C. Fritzinger (U.H.: University of Hawaii at Manoa)H-Index: 13
view all 6 authors...
3 CitationsSource
62 CitationsSource
#1William J. Cook (UAB: University of Alabama at Birmingham)H-Index: 38
#2Nicholas Galakatos (Novartis)H-Index: 4
Last. Steven E. Ealick (Cornell University)H-Index: 37
view all 5 authors...
The anaphylatoxin C5a is derived from the complement component C5 during activation of the complement cascade. It is an important component in the pathogenesis of a number of inflammatory diseases. NMR structures of human and porcine C5a have been reported; these revealed a four-helix bundle stabilized by three disulfide bonds. The crystal structure of human desArg-C5a has now been determined in two crystal forms. Surprisingly, the protein crystallizes as a dimer and each monomer in the dimer ha...
18 CitationsSource
#1Bert J. C. Janssen (UU: Utrecht University)H-Index: 18
#2Lucio Gomes (UU: Utrecht University)H-Index: 4
Last. Piet Gros (UU: Utrecht University)H-Index: 47
view all 8 authors...
Immune protection by the complement system critically depends on assembly of C3 convertases on the surface of pathogens and altered host cells. These short-lived protease complexes are formed through pro-convertases, which for the alternative pathway consist of the complement component C3b and the pro-enzyme factor B (FB). Here, we present the crystal structure at 2.2-A resolution, small-angle X-ray scattering and electron microscopy (EM) data of the pro-convertase formed by human FB and cobra v...
50 CitationsSource
#1Jin Wu (UU: Utrecht University)H-Index: 7
#2You-Qiang Wu (UPenn: University of Pennsylvania)H-Index: 7
Last. Piet Gros (UU: Utrecht University)H-Index: 47
view all 6 authors...
Factor H (FH) is an abundant regulator of complement activation and protects host cells from self-attack by complement. Here we provide insight into the regulatory activity of FH by solving the crystal structure of the first four domains of FH in complex with its target, complement fragment C3b. FH interacted with multiple domains of C3b, covering a large, extended surface area. The structure indicated that FH destabilizes the C3 convertase by competition and electrostatic repulsion and that FH ...
242 CitationsSource
Cited By55
Newest
#1Martin Parnov Reichhardt (University of Oxford)H-Index: 6
#2Steven G. Johnson (University of Oxford)H-Index: 74
Last. Susan M. Lea (University of Oxford)H-Index: 47
view all 9 authors...
The complement system is a crucial part of innate immune defenses against invading pathogens. The blood-meal of the tick Rhipicephalus pulchellus lasts for days, and the tick must therefore rely on inhibitors to counter complement activation. We have identified a class of inhibitors from tick saliva, the CirpT family, and generated detailed structural data revealing their mechanism of action. We show direct binding of a CirpT to complement C5 and have determined the structure of the C5–CirpT com...
Source
#1Debabrata Dutta (IIT-KGP: Indian Institute of Technology Kharagpur)H-Index: 4
#2Devdeep Mukherjee (IIT-KGP: Indian Institute of Technology Kharagpur)H-Index: 3
Last. Amit Das (IIT-KGP: Indian Institute of Technology Kharagpur)H-Index: 40
view all 6 authors...
Source
#1Keith Jendza (Novartis)H-Index: 2
#2Mitsunori Kato (Novartis)H-Index: 3
Last. Gregory A. Michaud (Novartis)H-Index: 15
view all 27 authors...
The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria. Here, we report the identification, optimization and mechanism of action for the first small-molecule inhibitor of C5 complement protein.
Source
#1Martin Parnov Reichhardt (University of Oxford)H-Index: 6
#2Steven G. Johnson (University of Oxford)H-Index: 74
Last. Susan M. Lea (University of Oxford)H-Index: 47
view all 9 authors...
The complement system is a crucial part of innate immune defences against invading pathogens. The blood-meal of the tick Rhipicephalus pulchellus lasts for days, and the tick must therefore rely on inhibitors to counter complement activation. We have identified a novel class of inhibitors from tick saliva, the CirpT family, and generated detailed structural data revealing their mechanism of action. We show direct binding of a CirpT to complement C5 and have determined the structure of the C5-Cir...
Source
#1D.A.C. Heesterbeek (UU: Utrecht University)H-Index: 2
#2Bart W. Bardoel (UU: Utrecht University)H-Index: 11
Last. Suzan H. M. Rooijakkers (UU: Utrecht University)H-Index: 28
view all 11 authors...
Abstract The immune system kills bacteria by the formation of lytic membrane attack complexes (MACs), triggered when complement enzymes cleave C5. At present, it is not understood how the MAC perturbs the composite cell envelope of Gram‐negative bacteria. Here, we show that the role of C5 convertase enzymes in MAC assembly extends beyond the cleavage of C5 into the MAC precursor C5b. Although purified MAC complexes generated from preassembled C5b6 perforate artificial lipid membranes and mammali...
9 CitationsSource
#1Laure Yatime (AU: Aarhus University)H-Index: 13
#2Nicolas S. Merle (French Institute of Health and Medical Research)H-Index: 8
Last. Gregers R. Andersen (AU: Aarhus University)H-Index: 36
view all 10 authors...
The complement system is an efficient anti-microbial effector mechanism. On the other hand abnormal complement activation is involved in the pathogenesis of multiple inflammatory and hemolytic diseases. As general inhibition of the complement system may jeopardize patient health due to increased susceptibility to infections, the development of pathway-specific complement therapeutics has been a long-lasting goal over the last decades. In particular, pathogen mimicry has been considered as a prom...
Source
#1Nehemiah Zewde (UCR: University of California, Riverside)H-Index: 2
#2Rohith R. Mohan (UCR: University of California, Riverside)H-Index: 3
Last. Dimitrios Morikis (UCR: University of California, Riverside)H-Index: 32
view all 3 authors...
The complex between complement system proteins C5b and C6 is the cornerstone for the assembly of the membrane attack complex (MAC, also known as C5b6789n). MAC is the terminal product of three converging pathways of the complement system and functions as a pore forming complex on cell surfaces, as a response of the immune system in fighting pathogens. However, when proper regulation of the complement system is compromised, MAC also attacks host tissues and contributes to several complement-media...
1 CitationsSource
#1Alex Macpherson (University of Bath)H-Index: 1
#2Xiaofeng LiuH-Index: 22
view all 9 authors...
1 CitationsSource
#1Seline A. Zwarthoff (UU: Utrecht University)H-Index: 2
#2Evelien T.M. Berends (UU: Utrecht University)H-Index: 9
Last. Ronald D. Gorham (UU: Utrecht University)H-Index: 10
view all 9 authors...
Complement is essential for the protection against infections; however, dysregulation of complement activation can cause onset and progression of numerous inflammatory diseases. Convertase enzymes play a central role in complement activation and produce the key mediators of complement: C3 convertases cleave C3 to generate chemoattractant C3a and label target cells with C3b, which promotes phagocytosis; C5 convertases cleave C5 into chemoattractant C5a, and C5b, which drives formation of the memb...
5 CitationsSource
#1Rasmus K. JensenH-Index: 5
#2Rasmus Pihl (AU: Aarhus University)H-Index: 2
Last. Gregers R. AndersenH-Index: 36
view all 8 authors...
2 CitationsSource