Abstract
Serum mannose-binding protein (MBP) initiates the lectin branch of the complement cascade by binding to sugars on the surfaces of microorganisms and activating two MBP-associated serine proteases (MASP-1 and MASP-2). Rat serum MBP consists of oligomers containing up to four copies of a subunit that is composed of three identical polypeptide chains. Biophysical analysis of intact and truncated MASPs indicates that each MASP is a homodimer that is stabilized through interactions involving an N-terminal CUB domain. The binding sites for MBP are formed from the three N-terminal MASP domains, in which two CUB modules interact with MBP. Each MASP dimer contains binding sites for two MBP subunits. Both sites must be occupied by subunits from a single MBP oligomer to form a stable complex. Thus, the smallest functional unit for complement activation consists of MBP dimers bound to MASP-1 or MASP-2 homodimers. Trimers and tetramers of MBP form complexes containing up to two MASPs. The results reveal how MASP-1 and MASP-2 can function independently to activate the complement cascade.
Highlights
Mannose-binding protein (MBP)1 is a key component of the innate immune response
The results reveal how MASP-1 and MASP-2 can function independently to activate the complement cascade
Defining Minimum mannose-binding protein (MBP)-binding Units of MASP-1 and MASP-2—The first step toward dissecting the MBP/MASP interaction was to reconstitute the MBP1⁄7MASP complex from purified components
Summary
Mannose-binding protein (MBP) is a key component of the innate immune response. It binds to sugars on the surfaces of pathogenic microorganisms and activates complement by an antibody-independent mechanism [1, 2]. A second MBP, found in the liver, has been identified in rats and other mammals This protein is designated MBP-C and consists of a single trimeric subunit that does not form larger oligomers. MASPs bind Ca2ϩ through interactions that probably involve the EGF-like domains [13]. Studies using truncated proteins have shown that MASP-1 and MASP-2 bind to MBP in a Ca2ϩ-dependent manner through interactions involving the CUB and EGF-like domains [13, 14]. Fragments encompassing these regions are Ca2ϩ-independent homodimers that are stabilized by interactions involving the two N-terminal domains. A complex between two MBP subunits and either a MASP-1 or MASP-2 dimer is sufficient to form a functional unit that is capable of becoming activated
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