Simultaneous Activation of Complement and Coagulation by MBL-Associated Serine Protease 2

Krarup, Anders; Wallis, Russell; Presanis, Julia S.; Gál, Péter; Sim, Robert B.

doi:10.1371/journal.pone.0000623

Cited by 239 publications

(232 citation statements)

References 35 publications

(40 reference statements)

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“…It has been shown that MASP-1 is the main activator of MASP-2 Heja et al, 2012; Megyeri et al, 2013) and that MASP-2 is able to cleave prothrombin (Krarup et al, 2007). Therefore, we wanted to test whether the effects of MASP-1 on clotting observed in WB and PPP could be due to MASP-1-mediated activation of MASP-2 and not due to direct action of MASP-1 itself.…”

Section: Effects Of Masp-1 Are Prothrombin-dependentmentioning

confidence: 98%

“…In the lectin pathway, mannose binding lectin (MBL) and ficolins recognize target molecules on foreign and/or altered surfaces and thereby induce activation of the MBL-associated serine proteases (MASPs) MASP-1, MASP-2, and MASP-3 (Krarup et al, 2007). MASPs 1-3 and the enzymatically inactive MBL-associated proteins MAp19 and MAp44 are alternative splicing products from two genes: MASP-1/MASP-3/Map44 and MASP2/MAp19 (Stover et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…MASP-2 was also shown to cleave prothrombin in a similar way to activated factor X (FXa) and hence to promote clot formation (Krarup et al, 2007;Yongqing et al, 2012). In contrast, the function of MASP-3 remains unclear so far.…”

Section: Introductionmentioning

confidence: 99%

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MASP-1 of the complement system promotes clotting via prothrombin activation

Jenny

Dobó

Gál

et al. 2015

Molecular Immunology

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associated serine protease; MBL, mannose binding lectin; MCF, maximum clot firmness; MES, 2-(N-Morpholino)-ethanesulfonic acid; PAR4, protease activated receptor 4; PPP, platelet-poor plasma; PT-DP, Prothrombin-depleted plasma; PVDF, polyvinylidene difluoride; rMASP-1cf, MASP-1 catalytic fragment; SGMI, Schistocerca gregaria protease inhibitor (SGPI)-based MASPinhibitor; WB, whole blood. AbstractMannan-binding lectin-associated serine protease-1 (MASP-1), a protein of the complement lectin pathway, resembles thrombin in terms of structural features and substrate specificity, and it has been shown to activate coagulation factors. Here we studied the effects of MASP-1 on clot formation in whole blood (WB) and platelet-poor plasma (PPP) by thrombelastography and further elucidated the underlying mechanism. Cleavage of prothrombin by MASP-1 was investigated by SDS-PAGE and N-terminal sequencing of cleavage products. Addition of MASP-1 or thrombin to WB and PPP shortened the clotting time and clot formation time significantly compared to recalcified-only samples. The combination of MASP-1 and thrombin had additive effects. In a purified system, MASP-1 was able to induce clotting only in presence of prothrombin. Analysis of MASP-1-digested prothrombin confirmed that MASP-1 cleaves prothrombin at three cleavage sites. In conclusion, we have shown that MASP-1 is able to induce and promote clot formation measured in a global setting using the technique of thrombelastography. We further confirmed that MASP-1-induced clotting is dependent on prothrombin. Finally, we have demonstrated that MASP-1 cleaves prothrombin and identified its cleavage sites, suggesting that MASP-1 gives rise to an alternative active form of thrombin by cleaving at the cleavage site R393.

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Section: Effects Of Masp-1 Are Prothrombin-dependentmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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MASP-1 of the complement system promotes clotting via prothrombin activation

Jenny

Dobó

Gál

et al. 2015

Molecular Immunology

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“…Although the functions of the other MASPs are poorly understood, MASP-1 appears to play a role as an amplifier of complement activation (6, 7). Additionally, MASP-1 is able to cleave fibrinogen to fibrin, whereas MASP-2 is able to generate active thrombin by cleavage of prothrombin (8,9). No conclusive biological function has yet been attributed to MASP-3 and sMAP.…”

mentioning

confidence: 99%

A Novel Mannose-binding Lectin/Ficolin-associated Protein Is Highly Expressed in Heart and Skeletal Muscle Tissues and Inhibits Complement Activation

Skjoedt

Hummelshøj

Palarasah

et al. 2010

Journal of Biological Chemistry

139

146

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The human lectin complement pathway involves circulating complexes consisting of mannose-binding lectin (MBL) or three ficolins (ficolin-1, -2, and -3) in association with three MBL/ ficolin-associated serine proteases (MASP) (MASP-1, -2, and -3) and a nonenzymatic sMAP. MASP-1 and MASP-3 (MASP1 isoforms 1 and 2, respectively) are splice variants of the MASP1 gene, whereas MASP-2 and sMAP are splice variants of the MASP2 gene. We have identified a novel serum protein of 45 kDa that is associated with MBL and the ficolins. This protein is named MBL/ficolin-associated protein 1 (MAP-1 corresponding to MASP1 isoform 3). The transcript generating MAP-1 (MASP1_v3) contains exons 1-8 and a novel exon encoding an in-frame stop codon. The corresponding protein lacks the serine protease domains but contains most of the common heavy chain of MASP-1 and MASP-3. Additionally MAP-1 contains 17 unique C-terminal amino acids. By use of quantitative PCR and MAP-1-specific immunohistochemistry, we found that MAP-1 is highly expressed in myocardial and skeletal muscle tissues as well as in liver hepatocytes with a different expression profile than that observed for MASP-1 and MASP-3. MAP-1 co-precipitated from human serum with MBL, ficolin-2, and ficolin-3, and recombinant MAP-1 was able to inhibit complement C4 deposition via both the ficolin-3 and MBL pathway. In conclusion we have identified a novel 45-kDa serum protein derived from the MASP1 gene, which is highly expressed in striated muscle tissues. It is found in complex with MBL and ficolins and may function as a potent inhibitor of the complement system in vivo.Activation of the complement system is accomplished via three different initiation pathways: the alternative pathway, the classical pathway, and the lectin pathway (1). In humans, four recognition molecules of the lectin pathway have been described: mannose-binding lectin (MBL), 3 ficolin-1 (also called M-ficolin), ficolin-2 (also called L-ficolin), and ficolin-3 (also called H-ficolin or Hakata antigen) (2). MBL and the ficolins bind structures on different classes of microorganisms and are involved in sequestration and removal of dying host cells (2, 3). Three MBL/ficolin-associated serine proteases have been described so far (MASP-1, MASP-2, and MASP-3), as well as a protein lacking a serine protease domain named sMAP or MAp19 (4). Present consensus places MASP-2 as the main initiator of the lectin complement pathway by cleaving C4 and C2 to form the C4b2a complex leading to further downstream complement activation (5). Although the functions of the other MASPs are poorly understood, MASP-1 appears to play a role as an amplifier of complement activation (6, 7). Additionally, MASP-1 is able to cleave fibrinogen to fibrin, whereas MASP-2 is able to generate active thrombin by cleavage of prothrombin (8,9). No conclusive biological function has yet been attributed to MASP-3 and sMAP. MASP-1 and MASP-2 were originally named after their association with MBL (5, 10). Subsequently, MASP-3 and sMAP (also named Map19) we...

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“…Similarly, MASP-1 can also activate TAFI (Hess et al, 2012b) which inhibits fibrin-dependent fibrinolysis by tissue plasminogen activator (t-PA). It was reported earlier that MASP-2 is able to activate prothrombin (Krarup et al, 2007).…”

Section: Masp-1 Interacts With Coagulation Factors and Affects Clot Fmentioning

confidence: 85%

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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Simultaneous Activation of Complement and Coagulation by MBL-Associated Serine Protease 2

Cited by 239 publications

References 35 publications

MASP-1 of the complement system promotes clotting via prothrombin activation

MASP-1 of the complement system promotes clotting via prothrombin activation

A Novel Mannose-binding Lectin/Ficolin-associated Protein Is Highly Expressed in Heart and Skeletal Muscle Tissues and Inhibits Complement Activation

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

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