Distinct pathways of mannan-binding lectin (MBL)- and C1-complex autoactivation revealed by reconstitution of MBL with recombinant MBL-associated serine protease-2

Mannan-binding lectin (MBL) plays a pivotal role in innate immunity by acti vating complement after binding carbohydrate moieties on pathogenic bacteri a and viruses. Structural similarities shared by MBL and C1 complexes and b y the MBL- and C1q-associated serine proteases, MEL-associated serine prote ase (MASP)-1 and MASP-2, and C1r and C1s, respectively, have led to the exp ectation that the pathways of complement activation by MBL and C1 complexes are likely to be very similar. We have expressed rMASP-2 and show that, wh ereas C1 complex autoactivation proceeds via a two-step mechanism requiring proteolytic activation of both C1r and C1s, reconstitution with MASP-2 alo ne is sufficient for complement activation by MEL. The results suggest that the catalytic activities of MASP-2 split between the two proteases of the C1 complex during the course of vertebrate complement evolution.