3GOV

Crystal structure of the catalytic region of human MASP-1

Summary for 3GOV

• Entry DOI: 10.2210/pdb3gov/pdb
• Descriptor: MASP-1, GLYCEROL, ... (4 entities in total)
• Functional Keywords: complement, serine protease, beta barrel, hydrolase, hydroxylation, immune response, innate immunity, sushi, coagulation, complement pathway, disulfide bond, egf-like domain, glycoprotein, protease
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P48740 P48740
• Total number of polymer chains: 2
• Total formula weight: 45721.33

Authors

Harmat, V.,Dobo, J.,Beinrohr, L.,Sebestyen, E.,Zavodszky, P.,Gal, P. (deposition date: 2009-03-20, release date: 2009-06-09, Last modification date: 2024-11-06)

Primary citation

Dobo, J.,Harmat, V.,Beinrohr, L.,Sebestyen, E.,Zavodszky, P.,Gal, P.
MASP-1, a promiscuous complement protease: structure of its catalytic region reveals the basis of its broad specificity.
J.Immunol., 183:1207-1214, 2009

PubMed Abstract: 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 A 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.

PubMed: 19564340
DOI: 10.4049/jimmunol.0901141

Experimental method

X-RAY DIFFRACTION (2.55 Å)