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MASP1 (MBL-associated serine protease 1)
M Matsushita1, Y Endo, T Fujita
1Department of Biochemistry, Fukushima Medical University, Japan.
Abstract:
Mannose-binding lectin (MBL) is a serum component which participates in innate immunity by activating complement via a novel pathway. Human MBL forms complexes with two types of serine proteases termed MASP (MBL-associated serine protease). These two proteases, MASP1 and MASP2, are structurally similar to one another as well as to C1r and C1s. Together, MASP, C1r and C1s constitute a novel serine protease family. It is likely that human MASP1 is able to activate C3, while human MASP2 cleaves C4, although further functional studies are required to confirm this. Based on the analysis of MASP cDNA of vertebrates and ascidians, the MASP/C1r/C1s family can be classified into two groups. The first group is characterized by a histidine loop in its serine protease domain, an active-center serine encoded by TCN, and a proline as the amino acid residue at the-3 position from the active serine. Human MASP1, mouse MASP1, Xenopus MASP1 and ascidian MASPs all belong to this group. MASP of the second group has structural features which are distinct from those of the first group: an absence of a histidine loop, an active-serine encoded by AGY, and an alanine or valine as the amino acid residue at the -3 position from the active-serine. The second group includes human MASP2, Xenopus MASP2, carp MASP, shark MASP, C1r and C1s. The TCN-type of MASP may have emerged prior to the AGY-type as an ancestral protease of the MASP/C1r/C1s family and played a crucial role in cleaving C3.
Insights
Mannose-binding lectin (MBL)-associated serine proteases (MASPs) are key to innate immunity. MASP1 and MASP2 proteases are classified into two distinct groups based on structural and functional differences, with MASP1 potentially being an ancestral C3-cleaving protease.
Area of Science:
- Immunology
- Biochemistry
- Molecular Biology
Background:
- Mannose-binding lectin (MBL) is a crucial component of the innate immune system.
- MBL activates complement through a unique pathway involving MBL-associated serine proteases (MASPs).
- MASPs, specifically MASP1 and MASP2, are structurally related to C1r and C1s, forming a novel serine protease family.
Purpose of the Study:
- To investigate the structural and functional classification of the MASP/C1r/C1s serine protease family.
- To elucidate the evolutionary relationship and potential ancestral roles of MASP proteases.
Main Methods:
- Comparative analysis of MASP cDNA sequences from various vertebrates and ascidians.
- Identification of conserved structural features within the serine protease domains, including histidine loops and active-serine encoding.
Main Results:
- Two distinct groups within the MASP/C1r/C1s family were identified based on sequence analysis.
- Group 1 (e.g., human MASP1) is characterized by a histidine loop and TCN-encoded active serine, suggesting a role in C3 activation.
- Group 2 (e.g., human MASP2, C1r, C1s) possesses different structural features, including an AGY-encoded active serine.
Conclusions:
- The MASP/C1r/C1s family exhibits significant structural divergence, leading to two distinct functional groups.
- The TCN-type MASP, exemplified by MASP1, likely represents an ancestral protease that predates the AGY-type and was pivotal in C3 cleavage.
- MASP2 is likely involved in C4 cleavage, though further functional validation is necessary.