To date three serine proteases, namely MASP-1, MASP-2 and MASP-3 (Matsushita and Fujita, 1992; Thiel et al., 1997; Dahl et al, 2001) and a non-enzymatic component, MAp19 (Stover et al., 1999) were found to be associated with MBL. In a recent study it has been demonstrated that in serum, MASP-2 is entirely complexed with either MBL or ficolins (M0ller-Kristensen et al., 2003), whereas MASP-1 circulates in both bound in unbound forms (Terai et al., 1997). Investigating MBL/MASPs complexes, in sucrose gradient experiments MASP-1 and MAp19 were found to be associated with smaller MBL oligomers, whereas MASP-2 and MASP-3 were in the same fraction with larger MBL oligomers (Dahl et al., 2001).
Previously, it has been suggested that MASP-1 is involved in the complement activation through the direct cleavage of C3 (Matsushita and Fujita, 1995; Matsushita et al., 2000), but independent in vitro experiments showed that this has a very low probability in vivo (Rossi et al., 2001, Ambrus et al., 2003). Although MASP-1 is a more efficient peptidase than MASP-2 (Ambrus et al., 2003) it does not display any efficient complement activating cleavages. Recently, a non-complement substrate of MASP-1 has been identified. It has been shown that MASP-1 cleaves fibrinogen at about 10-20% of the efficiency of thrombin, which might play a physiologically important role (Hajela et al., 2002). The MBL independent function of MASP-1 is in accordance with the observation that the major portion of MASP-1 is not bound to MBL (Terai et al., 1997).
MASP-2 is the key protease of the lectin pathway of complement activation. Its capacity to autoactivate, cleave C4 and C2 (Vorup-Jensen et al., 2000) incorporate all the functions conveyed by two proteases in the classical pathway of complement activation, C1r and C1s. Our knowledge about the substrate specificity of MASP-2 in terms of natural substrates has changed little from what was suggested in the seminal paper of Thiel and coworkers (Thiel et al., 1997). Nevertheless, recent works have provided an insight at the submolecular level how its function is actually accomplished. It is clear now, that MASP-1 and MASP-2, as well as MApl9 form homodimers and associate with MBL in a dependent manner through their CUB-EGF domains (Wallis and Dodd, 2000; Chen and Wallis, 2001; Thielens et al., 2001). It has been shown, that the autoactivation and the C2 cleaving property of MASP-2 is conveyed entirely through its serine protease (SP) domain, whereas in the efficient cleavage of C4 the second complement control protein (CCP2) module plays an important role (Ambrus et al., 2003). Recently, multidomain fragments of both the N-terminal and C-terminal parts have been crystallized and their structure determined (Feinberg et al., 2003; Harmat et al., unpublished).
An unclarified issue is the substrate specificity of MASP-3, as no natural substrate for this protease component has been identified, yet. It has been proposed that MASP-3 is a regulator of the lectin pathway activation through its competitive inhibition of MASP-2 binding to MBL (Dahl et al., 2001).
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