Natural Substrates and Inhibitors of Mannan-Binding Lectin-Associated Serine Protease-1 and -2: A Study on Recombinant Catalytic Fragments

Ambrus, Géza; Gál, Péter; Kojima, Mayumi; Szilágyi, Katalin; Balczer, Júlia; Antal, József; Gráf, László; Laich, Andreas; Moffatt, Beryl E.; Schwaeble, Wilhelm; Sim, Robert B.; Závodszky, Péter

doi:10.4049/jimmunol.170.3.1374

Cited by 202 publications

(228 citation statements)

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“…Three types of MASPs are associated in the proenzyme form with MBL: MASP-1, MASP-2, and MASP-3. The exact function of MASP-1 and MASP-3 has yet to be determined, although MASP-1 has been shown to cleave C3 weakly (12,13). MASP-2 has been shown to cleave C2 and C4 (12)(13)(14).…”

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confidence: 99%

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Activation of Complement Component C5

Rawal

Rajagopalan

Salvi

2008

Journal of Biological Chemistry

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Although the initiating complex of lectin pathway (called M1 in this study) generates C3/C5 convertases similar to those assembled by the initiating complex (C1) of the classical pathway, activation of complement component C5 via the lectin pathway has not been examined. In the present study kinetic analysis of lectin pathway C3/C5 convertases assembled on two surfaces (zymosan and sheep erythrocytes coated with mannan (E Man )) revealed that the convertases (ZymM1,C4b,C2a and E Man M1,C4b,C2a) exhibited a similar but weak affinity for the substrate, C5 indicated by a high K m (2.73-6.88 M). Very high affinity C5 convertases were generated when the low affinity C3/C5 convertases were allowed to deposit C3b by cleaving native C3. These C3b-containing convertases exhibited K m (0.0086 -0.0075 M) well below the normal concentration of C5 in blood (0.37 M). Although kinetic parameters, K m and k cat , of the lectin pathway C3/C5 convertases were similar to those reported for classical pathway C3/C5 convertases, studies on the ability of C4b to bind C2 indicated that every C4b deposited on zymosan or E Man was capable of forming a convertase. These findings differ from those reported for the classical pathway C3/C5 convertase, where only one of four C4b molecules deposited formed a convertase. The potential for four times more amplification via the lectin pathway than the classical pathway in the generation of C3/C5 convertases and production of pro-inflammatory products, such as C3a, C4a, and C5a, implies that activation of complement via the lectin pathway might be a more prominent contributor to the pathology of inflammatory reactions.The lectin pathway (1), a more recent discovery of complement, is activated when mannan-binding lectin (MBL), 2 a pattern-recognition molecule, binds to sugars present on the cell surface of microorganisms (2-8). In plasma, MBL circulates in complex with serine proteases called MBL-associated serine proteases (MASPs) (9 -11). We will refer to this complex as M1 in keeping with the complement nomenclature. Three types of MASPs are associated in the proenzyme form with MBL: MASP-1, MASP-2, and MASP-3. The exact function of MASP-1 and MASP-3 has yet to be determined, although MASP-1 has been shown to cleave C3 weakly (12, 13). MASP-2 has been shown to cleave C2 and C4 (12-14). Binding of MBL⅐MASP complexes to sugar residues present on the cell surfaces of microorganisms results in a conformational change of MBL (15, 16), which activates MASP-2. Activated MASP-2 cleaves C4 and C2 resulting in the formation of C3/C5 convertases (C4b,C2a) (17-19).C3/C5 convertases are enzymes that cleave C3 and C5. Products generated upon the cleavage of C3 and C5 (C3a, C3b, C5a, and C5b) have important biological activities (20). C3b, the larger cleavage product of C3, opsonizes bacteria, whereas C3a, the smaller product, is an anaphylatoxin with important functions such as chemotaxis of mast cells and contraction of smooth muscle cells (21-24). C5b, the larger cleavage product of C5, initiates formation ...

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confidence: 99%

“…The exact function of MASP-1 and MASP-3 has yet to be determined, although MASP-1 has been shown to cleave C3 weakly (12,13). MASP-2 has been shown to cleave C2 and C4 (12)(13)(14). Binding of MBL⅐MASP complexes to sugar residues present on the cell surfaces of microorganisms results in a conformational change of MBL (15,16), which activates MASP-2.…”

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confidence: 99%

Activation of Complement Component C5

Rawal

Rajagopalan

Salvi

2008

Journal of Biological Chemistry

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“…It was also suggested that MASP-1 can cleave C3, generating C3b before the assembly of the C3 convertase complexes (Matsushita et al, 2000). Detailed enzyme kinetic studies, however, revealed that although MASP-1 really cleaves C3, the catalytic efficiency (k cat /K M ) of this reaction is very low (3X10 2 M -1 s -1 ) (Ambrus et al, 2003) compared to the efficiency of a real C3 convertase, which is three orders of magnitude higher. This low C3…”

Section: The Mystery Surrounding the Role Of Masp-1mentioning

confidence: 99%

“…In contrast to MASP-1, MASP-2 has a partly occluded substrate binding cleft, and has only two major substrates -C2 and C4 (Ambrus et al, 2003). Therefore, it is not unexpected that MASP-2 does not cleave any PARs nor has any effects on endothelial cells (Megyeri et al, 2009).…”

Section: Only Masp-1 Activates Endothelial Cells Among Lectin Pathwaymentioning

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Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation

Dobó

Schroeder

Jenny

et al. 2014

Molecular Immunology

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MASP-1 is a versatile serine protease that cleaves a number of substrates in human blood. In recent years it became evident that besides playing a crucial role in complement activation MASP-1 also triggers other cascade systems and even cells to mount a more powerful innate immune response. In this review we summarize the latest discoveries about the diverse functions of this multi-faceted protease. Recent studies revealed that among MBLassociated serine proteases, MASP-1 is the one responsible for triggering the lectin pathway via its ability to rapidly autoactivate then cleave MASP-2, and possibly MASP-3. The crystal structure of MASP-1 explains its more relaxed substrate specificity compared to the related complement enzymes. Due to the relaxed specificity, MASP-1 interacts with the coagulation cascade and the kinin generating system, and it can also activate endothelial cells eliciting pro-inflammatory signaling.

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Lectin Complement Pathway Gene Profile of Donor and Recipient Determine the Risk of Bacterial Infections After Orthotopic Liver Transplantation†,‡

et al. 2010

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Infectious complications after orthotopic liver transplantation (OLT) are a major clinical problem. The lectin pathway of complement activation is liver-derived and a crucial effector of the innate immune defense against pathogens. Polymorphisms in lectin pathway genes determine their functional activity. We assessed the relationship between these polymorphic genes and clinically significant bacterial infections, i.e., sepsis, pneumonia, and intra-abdominal infection, and mortality within the first year after OLT, in relation to major risk factors in two cohorts from different transplant centers. Single-nucleotide polymorphisms in the mannose-binding lectin gene (MBL2), the ficolin-2 gene (FCN2), and the MBL-associated serine protease gene (MASP2) of recipients and donors were determined. Recipients receiving a donor liver in the principal cohort with polymorphisms in all three components i.e., MBL2 (XA/O; O/O), FCN216359T, and MASP21371A, had a cumulative risk of an infection of 75% as compared to 18% with wild-type donor livers (P 5 0.002), an observation confirmed in the second cohort (P 5 0.04). In addition, a genetic (mis)match between donor and recipient conferred a two-fold higher infection risk for each separate gene. Multivariate Cox analysis revealed a stepwise increase in infection risk with the lectin pathway gene profile of the donor (hazard ratio 5 4.52; P 5 8.1 3 10 26 ) and the donor-recipient (mis)match genotype (hazard ratio 5 6.41; P 5 1.9 3 10 27 ), independent from the other risk factors sex and antibiotic prophylaxis (hazard ratio > 1.7 and P < 0.02). Moreover, patients with a lectin pathway gene polymorphism and infection had a six-fold higher mortality (P 5 0.9 3 10 28 ), of which 80% was infectionrelated. Conclusion: Donor and recipient gene polymorphisms in the lectin complement pathway are major determinants of the risk of clinically significant bacterial infection and mortality after OLT. (HEPATOLOGY 2010;52:1100-1110 Abbreviations: CI, confidence interval; CSI, clinically significant bacterial infection; HR, hazard ratio; MASP, MBL-associated serine protease; MBL, mannosebinding lectin; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation; SNP, single-nucleotide polymorphism.From the

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Natural Substrates and Inhibitors of Mannan-Binding Lectin-Associated Serine Protease-1 and -2: A Study on Recombinant Catalytic Fragments

Cited by 202 publications

References 64 publications

Activation of Complement Component C5

Activation of Complement Component C5

Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation

Lectin Complement Pathway Gene Profile of Donor and Recipient Determine the Risk of Bacterial Infections After Orthotopic Liver Transplantation†,‡

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