Two Mechanisms for Mannose-binding Protein Modulation of the Activity of Its Associated Serine Proteases
Open Access
- 1 June 2004
- journal article
- Published by Elsevier BV
- Vol. 279 (25), 26058-26065
- https://doi.org/10.1074/jbc.m401318200
Abstract
Serum mannose-binding protein (MBP) neutralizes invading microorganisms by binding to cell surface carbohydrates and activating MBP-associated serine proteases-1, -2, and -3 (MASPs). MASP-2 subsequently cleaves complement components C2 and C4 to activate the complement cascade. To analyze the mechanisms of activation and substrate recognition by MASP-2, zymogen and activated forms have been produced, and MBP·MASP-2 complexes have been created. These preparations have been used to show that MBP modulates MASP-2 activity in two ways. First, MBP stimulates MASP-2 autoactivation by increasing the rate of autocatalysis when MBP·MASP-2 complexes bind to a glycan-coated surface. Second, MBP occludes accessory C4-binding sites on MASP-2 until activation occurs. Once these sites become exposed, MASP-2 binds to C4 while separate structural changes create a functional catalytic site able to cleave C4. Only activated MASP-2 binds to C2, suggesting that this substrate interacts only near the catalytic site and not at accessory sites. MASP-1 cleaves C2 almost as efficiently as MASP-2 does, but it does not cleave C4. Thus MASP-1 probably enhances complement activation triggered by MBP·MASP-2 complexes, but it cannot initiate activation itself.Keywords
This publication has 30 references indexed in Scilit:
- Alternative strategies for the characterization of associations in multicomponent solutions via measurement of sedimentation equilibriumPublished by Springer Science and Business Media LLC ,2008
- Stoichiometry of Complexes between Mannose-binding Protein and Its Associated Serine ProteasesPublished by Elsevier BV ,2001
- Interaction of Mannose-binding Protein with Associated Serine ProteasesPublished by Elsevier BV ,2000
- Characterization of Heterologous Protein–Protein Interactions Using Analytical UltracentrifugationMethods, 1999
- Mannose-binding lectin: the pluripotent molecule of the innate immune systemImmunology Today, 1996
- Biology of Animal LectinsAnnual Review of Cell Biology, 1993
- Genetic Deficiencies of the Complement System and Association with Disease-Early ComponentsInternational Reviews of Immunology, 1993
- The structural basis of the multiple forms of human complement component C4Cell, 1984
- The biochemistry of complementNature, 1978
- Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4Nature, 1970