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MASP-2, the C3 convertase generating protease of the MBLectin complement activating pathway
T Vorup-Jensen1, J C Jensenius, S Thiel
1Department of Medical Microbiology and Immunology, University of Aarhus, Denmark. vorup@biobase.dk
Abstract:
Mannan-binding lectin (MBL) activates the complement system through cleavage of C4 and C2. Until recently it was thought that only one serine protease in complex with MBL (MBL-associated serine protease, MASP) mediates complement activation, but with the finding of a second MBL-associated serine protease, MASP-2, the activation process appears more elaborate, possibly resembling that of the C1 complex. The two MASPs share the domain organisation of C1r and C1s and it may be speculated that interaction between the two MASPs is required for complement activation in the same manner as with the C1 proteases. We have demonstrated that MASP-2 is a C4 cleaving component of the MBL/MASP complex. By analogy, one may thus speculate that, upon binding of MBL to carbohydrate, MASP-1 autoactivates and then activates MASP-2, but there is as yet no evidence for this. The components of C1 are present in serum in approximately equimolar amounts, whereas MASP-1 is in large excess over MBL. Pairwise comparison of the four proteases shows the primary structures to be approximately 40% identical. Phylogenetic analysis indicates that MASP-2 is closer to C1r and C1s than is MASP-1, but no particular association between MASP-2 and the C4 cleaving enzyme, C1s, can be deduced from sequence comparison.
Insights
Mannan-binding lectin (MBL) and its associated proteases (MASPs) activate the complement system. MASP-2 is confirmed as the C4 cleaving component, suggesting a more complex activation pathway.
Area of Science:
- Immunology
- Biochemistry
- Molecular Biology
Background:
- Mannan-binding lectin (MBL) initiates complement activation via C4 and C2 cleavage.
- Previously, only one MBL-associated serine protease (MASP) was known; MASP-2 has since been identified.
- The MBL/MASP complex's activation mechanism may resemble the C1 complex.
Purpose of the Study:
- To investigate the role of MASP-2 in MBL-mediated complement activation.
- To elucidate the functional relationship between MASP-1 and MASP-2.
- To compare the structural and phylogenetic relationships of MASPs with C1 proteases.
Main Methods:
- Demonstration of MASP-2 as the C4 cleaving component within the MBL/MASP complex.
- Analysis of domain organization and sequence identity between MASPs and C1 proteases.
- Phylogenetic analysis to infer evolutionary relationships.
Main Results:
- MASP-2 was confirmed as the C4 cleaving component of the MBL/MASP complex.
- MASP-1 is present in significant excess over MBL in serum.
- Phylogenetic analysis suggests MASP-2 is more closely related to C1r and C1s than MASP-1.
Conclusions:
- MASP-2 plays a direct role in cleaving C4, a key step in complement activation.
- The MBL/MASP system's activation may involve intricate interactions between MASP-1 and MASP-2.
- While MASP-2 shares similarities with C1s, direct functional associations require further investigation.