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MASP-1, a Promiscuous Complement Protease: Structure of Its Catalytic Region Reveals the Basis of Its Broad Specificity¹

József Dobó^2,3,*, Veronika Harmat^3,, László Beinrohr^*, Edina Sebestyén^*, Péter Závodszky^* and Péter Gál^2,*

*Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary; and Protein Modeling Group, Hungarian Academy of Sciences, and Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary

Mannose-binding lectin (MBL)-associated serine protease (MASP)-1 is an abundant component of the lectin pathway of complement. The related enzyme, MASP-2 is capable of activating the complement cascade alone. Though the concentration of MASP-1 far exceeds that of MASP-2, only a supporting role of MASP-1 has been identified regarding lectin pathway activation. Several non-complement substrates, like fibrinogen and factor XIII, have also been reported. MASP-1 belongs to the C1r/C1s/MASP family of modular serine proteases; however, its serine protease domain is evolutionary different. We have determined the crystal structure of the catalytic region of active MASP-1 and refined it to 2.55 Å resolution. Unusual features of the structure are an internal salt bridge (similar to one in factor D) between the S1 Asp189 and Arg224, and a very long 60-loop. The functional and evolutionary differences between MASP-1 and the other members of the C1r/C1s/MASP family are reflected in the crystal structure. Structural comparison of the protease domains revealed that the substrate binding groove of MASP-1 is wide and resembles that of trypsin rather than early complement proteases explaining its relaxed specificity. Also, MASP-1's multifunctional behavior as both a complement and a coagulation enzyme is in accordance with our observation that antithrombin in the presence of heparin is a more potent inhibitor of MASP-1 than C1 inhibitor. Overall, MASP-1 behaves as a promiscuous protease. The structure shows that its substrate binding groove is accessible; however, its reactivity could be modulated by an unusually large 60-loop and an internal salt bridge involving the S1 Asp.

²Address correspondence and reprint requests to Dr. J. Dobó or Dr. P. Gál, Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Karolina út 29, H-1113, Budapest, Hungary. E-mail address: dobo{at}enzim.hu or gal{at}enzim.hu

¹ Data from the European Community (Research Infrastructure Action under the FP6 "Structuring the European Research Area Specific Programme" to the EMBL Hamburg Outstation, Contract Number RII3-CT-2004-506008). This work was supported by the Ányos Jedlik Grant NKFP_07_1-MASPOK07 of the Hungarian National Office for Research and Technology, and by the Hungarian Scientific Research Fund Grants NK77978, NI61915, K72973, F67937, and NK67800.

³ J.D. and V.H. contributed equally to this work.

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