Match!

Structural basis for activation of the complement system by component C4 cleavage.

Published on Sep 18, 2012in Proceedings of the National Academy of Sciences of the United States of America9.58
· DOI :10.1073/pnas.1208031109
Rune T. Kidmose6
Estimated H-index: 6
,
N.S. Laursen6
Estimated H-index: 6
+ 7 AuthorsGregers R. Andersen36
Estimated H-index: 36
Abstract
An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 A from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C–CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme–substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen–antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.
  • References (34)
  • Citations (68)
📖 Papers frequently viewed together
1,797 Citations
200543.07Nature
8 Authors (Bert J. C. Janssen, ..., Piet Gros)
348 Citations
107 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References34
Newest
#1Renee C. Duncan (Monash University, Clayton campus)H-Index: 10
#2Frida C. Mohlin (Lund University)H-Index: 7
Last. Lakshmi C. Wijeyewickrema (Monash University, Clayton campus)H-Index: 18
view all 9 authors...
The classical pathway of complement is crucial to the immune system, but it also contributes to inflammatory diseases when dysregulated. Binding of the C1 complex to ligands activates the pathway by inducing autoactivation of associated C1r, after which C1r activates C1s. C1s cleaves complement component C4 and then C2 to cause full activation of the system. The interaction between C1s and C4 involves active site and exosite-mediated events, but the molecular details are unknown. In this study, ...
18 CitationsSource
#1Dávid Héja (ELTE: Eötvös Loránd University)H-Index: 4
#2Veronika Harmat (ELTE: Eötvös Loránd University)H-Index: 20
Last. Gábor Pál (ELTE: Eötvös Loránd University)H-Index: 22
view all 9 authors...
The lectin pathway is an antibody-independent activation route of the complement system. It provides immediate defense against pathogens and altered self-cells, but it also causes severe tissue damage after stroke, heart attack, and other ischemia reperfusion injuries. The pathway is triggered by target binding of pattern recognition molecules leading to the activation of zymogen mannan-binding lectin-associated serine proteases (MASPs). MASP-2 is considered as the autonomous pathway-activator, ...
52 CitationsSource
#1Pavel V. Afonine (LBNL: Lawrence Berkeley National Laboratory)H-Index: 33
#2Ralf W. Grosse-Kunstleve (LBNL: Lawrence Berkeley National Laboratory)H-Index: 34
Last. Paul D. Adams (University of California, Berkeley)H-Index: 84
view all 10 authors...
phenix.refine is a program within the PHENIX package that supports crystallographic structure refinement against experimental data with a wide range of upper resolution limits using a large repertoire of model parameterizations. It has several automation features and is also highly flexible. Several hundred parameters enable extensive customizations for complex use cases. Multiple user-defined refinement strategies can be applied to specific parts of the model in a single refinement run. An intu...
2,022 CitationsSource
#1Søren E. Degn (AU: Aarhus University)H-Index: 18
#2Jens Chr. Jensenius (AU: Aarhus University)H-Index: 61
Last. Steffen Thiel (AU: Aarhus University)H-Index: 69
view all 3 authors...
Recent studies have revealed profound developmental consequences of mutations in genes encoding proteins of the lectin pathway of complement activation, a central component of the innate immune system. Apart from impairment of immunity against microorganisms, it is known that hereditary deficiencies of this system predispose one to autoimmune conditions. Polymorphisms in complement genes are linked to, for example, atypical hemolytic uremia and age-dependent macular degeneration. The complement ...
102 CitationsSource
Complement research experienced a renaissance with the discovery of a third activation route, the lectin pathway. We developed a unique model of total lectin pathway deficiency, a mouse strain lacking mannan-binding lectin-associated serine protease-2 (MASP-2), and analyzed the role of MASP-2 in two models of postischemic reperfusion injury (IRI). In a model of transient myocardial IRI, MASP-2–deficient mice had significantly smaller infarct volumes than their wild-type littermates. Mice deficie...
132 CitationsSource
#1N.S. Laursen (AU: Aarhus University)H-Index: 6
#2Kasper R. Andersen (AU: Aarhus University)H-Index: 15
Last. Gregers R. Andersen (AU: Aarhus University)H-Index: 36
view all 6 authors...
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...
55 CitationsSource
#1Søren HansenH-Index: 24
#2Lana SelmanH-Index: 4
Last. Uffe HolmskovH-Index: 49
view all 13 authors...
Collectins play important roles in the innate immune defense against microorganisms. Recently, a new collectin, collectin 11 (CL-11 or CL-K1), was identified via database searches. In present work, we characterize the structural and functional properties of CL-11. Under nonreducing conditions, in gel permeation chromatography recombinant CL-11 forms disulfide-linked oligomers of 100 and 200 kDa. A mAb-based ELISA estimates the concentration of CL-11 in plasma to be 2.1 μg/ml, and the presence of...
120 CitationsSource
#1Daniel Ricklin (UPenn: University of Pennsylvania)H-Index: 39
#2George Hajishengallis (University of Louisville)H-Index: 57
Last. John D. Lambris (UPenn: University of Pennsylvania)H-Index: 95
view all 4 authors...
Nearly a century after the significance of the human complement system was recognized we have come to realize that its versatile functions extend far beyond the elimination of microbes. Indeed, complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses, and sending `danger' signals, complement contributes substantially ...
1,797 CitationsSource
#1Renee C. Duncan (Monash University, Clayton campus)H-Index: 10
#2Frida C Bergstrom (Lund University)H-Index: 5
Last. Robert N. Pike (Monash University, Clayton campus)H-Index: 52
view all 6 authors...
The complement system is fundamental to both innate and adaptive immunity and can be initiated via the classical, lectin or alternative pathways. Cleavage of C4 by MASP-2, the initiating protease of the lectin pathway, is a crucial event in the activation of this pathway, preceding the eventual formation of the C3 convertase (C4bC2a) complex on the pathogen surface. Interactions required for the cleavage of C4 by MASP-2 are likely to be facilitated by the initial binding of C4 to an exosite on t...
18 CitationsSource
#1Mihaela S. Kojouharova (Sofia University)H-Index: 13
#2Kenneth B. M. Reid (Green Templeton College)H-Index: 3
Last. Mihaela Gadjeva (Brigham and Women's Hospital)H-Index: 30
view all 3 authors...
Abstract C1q, the initiator of the classical complement cascade, is a versatile molecule with numerous ligands and variety of functions. Recent mutagenesis, epitope mapping and structural data brought novel understanding of the molecular mechanisms of C1q binding to target molecules, and subsequent C1 activation. Evidence has emerged suggesting that residues located within the C1q apical surface, and the exposed side surface of the B chain, facilitate the interaction of C1q with the majority of ...
53 CitationsSource
Cited By68
Newest
#1Ditmer T. TalsmaH-Index: 3
#2Felix PoppelaarsH-Index: 8
Last. Marc A. SeelenH-Index: 23
view all 14 authors...
Source
#1Chen-Ming Lin (A&M: Texas A&M University)H-Index: 2
#2Maritess Arancillo (A&M: Texas A&M University)H-Index: 1
Last. Kevin Burgess (A&M: Texas A&M University)H-Index: 60
view all 4 authors...
Secondary structures tend to be recognizable because they have repeating structural motifs, but mimicry of these does not have to follow such well-defined patterns. Bioinformatics studies to match side-chain orientations of a novel hydantoin triazole chemotype (1) to protein-protein interfaces revealed it tends to align well across parallel and antiparallel sheets, like rungs on a ladder. One set of these overlays was observed for the protein-protein interaction uPA*uPAR. Consequently, chemotype...
Source
#1Dan-Dan Chen (CAS: Chinese Academy of Sciences)H-Index: 10
#2Yuan-Yuan Yao (CAS: Chinese Academy of Sciences)H-Index: 2
Last. Yong-An Zhang (CAS: Chinese Academy of Sciences)H-Index: 29
view all 3 authors...
Abstract The lectin pathway of complement activation is an important component of the innate immune response, which must be tightly controlled to maintain immune homeostasis. However, its control mechanisms have not been investigated in detail in bony fish. In this study, we identified and characterized two novel, phylogenetically conserved mannan-binding lectin (MBL)-associated proteins (MAps) of grass carp (Ctenopharyngodon idella), CiMAp27 and CiMAp39, which were truncated, alternatively-spli...
Source
#1Isabelle BallyH-Index: 17
#2Fabien DalonneauH-Index: 4
Last. Christine GaboriaudH-Index: 30
view all 11 authors...
Ehlers-Danlos syndromes (EDS) are clinically and genetically heterogeneous disorders characterised by soft connective tissue alteration like joint hypermobility and skin hyper-extensibility. We previously identified heterozygous missense mutations in the C1R and C1S genes, coding for the complement C1 proteases, in patients affected by periodontal EDS, a specific EDS subtype hallmarked by early severe periodontitis leading to premature loss of teeth and connective tissue alterations. Up to now, ...
Source
#1Thomas H. Sharp (LUMC: Leiden University Medical Center)H-Index: 13
#2Aimee L. Boyle (LEI: Leiden University)H-Index: 13
Last. Piet Gros (UU: Utrecht University)H-Index: 47
view all 6 authors...
Antigen binding by serum Ig-M (IgM) protects against microbial infections and helps to prevent autoimmunity, but causes life-threatening diseases when mistargeted. How antigen-bound IgM activates complement-immune responses remains unclear. We present cryoelectron tomography structures of IgM, C1, and C4b complexes formed on antigen-bearing lipid membranes by normal human serum at 4 °C. The IgM-C1-C4b complexes revealed C4b product release as the temperature-limiting step in complement activatio...
1 CitationsSource
#1Qi-Lin Zhang (Kunming University of Science and Technology)H-Index: 6
#2Zhi-Xiang Dong (Kunming University of Science and Technology)H-Index: 1
Last. Lian-Bing Lin (Kunming University of Science and Technology)H-Index: 2
view all 9 authors...
Abstract The gills of fish are large mucosal surfaces that are very important portals for pathogen entry. Investigations have shown that microRNAs (miRNAs) are key regulators of immune response to bacterial infections in the gills of fish; however, how miRNA expression changes in response to infection by Gram-positive bacteria remains largely unknown. To further investigate the immunological role of miRNAs in fish gills under pathogen stress induced by Gram-positive bacterial infection, this stu...
Source
#1Dana V. Rizk (UAB: University of Alabama at Birmingham)H-Index: 14
#2Nicolas Maillard (Jean Monnet University)H-Index: 6
Last. Robert J. Wyatt (UT: University of Tennessee)H-Index: 44
view all 7 authors...
IgA nephropathy is the most common form of primary glomerulonephritis worldwide and a common cause of end-stage renal disease. Evaluation of a kidney biopsy is necessary for diagnosis, with routine immunofluorescence-microscopy revealing dominant or co-dominant IgA immunodeposits usually with complement C3 and sometimes IgG and/or IgM. IgA nephropathy reduces life expectancy by more than 10 years and leads to kidney failure in 20-40% of patients within 20 years of diagnosis. There is accumulatin...
2 CitationsSource
#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
#1Elena Goicoechea de Jorge (Complutense University of Madrid)H-Index: 3
#2Alberto López Lera (Ciber)H-Index: 1
Last. S. Rodríguez de Córdoba (CSIC: Spanish National Research Council)H-Index: 57
view all 6 authors...
Abstract Genetic variability in the complement system and its association with disease has been known for more than 50 years, but only during the last decade have we begun to understand how this complement genetic variability contributes to the development of diseases. A number of reports have described important genotype-phenotype correlations that associate particular diseases with genetic variants altering specific aspects of the activation and regulation of the complement system. The detaile...
Source
#1József Dobó (MTA: Hungarian Academy of Sciences)H-Index: 23
#2Andrea Kocsis (MTA: Hungarian Academy of Sciences)H-Index: 7
Last. Péter Gál (MTA: Hungarian Academy of Sciences)H-Index: 32
view all 3 authors...
The complement system has moved into the focus of drug development efforts in the last decade, since its inappropriate or uncontrolled activation has been recognized in many diseases. Some of them are primarily complement-mediated rare diseases, such as paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis, and atypical hemolytic uremic syndrome. Complement also plays a role in various multifactorial diseases that affect millions of people worldwide, such as ischemia reperfusion injury (myo...
7 CitationsSource