The Serine Protease Domain of MASP-3: Enzymatic Properties and Crystal Structure in Complex with EcotinReportar como inadecuado

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Mannan-binding lectin MBL, ficolins and collectin-11 are known to associate with three homologous modular proteases, the MBL-Associated Serine Proteases MASPs. The crystal structures of the catalytic domains of MASP-1 and MASP-2 have been solved, but the structure of the corresponding domain of MASP-3 remains unknown. A link between mutations in the MASP1-3 gene and the rare autosomal recessive 3MC Mingarelli, Malpuech, Michels and Carnevale, syndrome, characterized by various developmental disorders, was discovered recently, revealing an unexpected important role of MASP-3 in early developmental processes. To gain a first insight into the enzymatic and structural properties of MASP-3, a recombinant form of its serine protease SP domain was produced and characterized. The amidolytic activity of this domain on fluorescent peptidyl-aminomethylcoumarin substrates was shown to be considerably lower than that of other members of the C1r-C1s-MASP family. The E. coli protease inhibitor ecotin bound to the SP domains of MASP-3 and MASP-2, whereas no significant interaction was detected with MASP-1, C1r and C1s. A tetrameric complex comprising an ecotin dimer and two MASP-3 SP domains was isolated and its crystal structure was solved and refined to 3.2 Å. Analysis of the ecotin-MASP-3 interfaces allows a better understanding of the differential reactivity of the C1r-C1s-MASP protease family members towards ecotin, and comparison of the MASP-3 SP domain structure with those of other trypsin-like proteases yields novel hypotheses accounting for its zymogen-like properties in vitro.

Autor: Christine Gaboriaud , Rajesh Kumar Gupta, Lydie Martin, Monique Lacroix, Laurence Serre, Florence Teillet, Gérard J. Arlaud, Vé



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