Multiple domains of MASP-2, an initiating complement protease, are required for interaction with its substrate C4

► Determination of the contribution of each catalytic domain of MASP-2 to binding and catalysis of C4. ► The CCP-2 and serine protease domains act cooperatively to facilitate high affinity binding to C4. ► The ability of the CCP domains to bind to C4 was directly demonstrated. ► Lys342 of CCP-1 plays a pivotal role in the binding of C4 by the CCP domains. ► The CCP domains bind C4b to facilitate cleavage of C2.