A true autoactivating enzyme: Structural insight into mannose-binding lectin-associated serine protease-2 activations

Péter Gál, Veronika Harmat, Andrea Kocsis, Tünde Bián, László Barna, Géza Ambrus, Barbara Végh, Júlia Balczer, Robert B. Sim, Gábor Náray-Szabó, Péter Závodszky

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Few reports have described in detail a true autoactivation process, where no extrinsic cleavage factors are required to initiate the autoactivation of a zymogen. Herein, we provide structural and mechanistic insight into the autoactivation of a multidomain serine protease: mannose-binding lectin-associated serine protease-2 (MASP-2), the first enzymatic component in the lectin pathway of complement activation. We characterized the proenzyme form of a MASP-2 catalytic fragment encompassing its C-terminal three domains and solved its crystal structure at 2.4 Å resolution. Surprisingly, zymogen MASP-2 is capable of cleaving its natural substrate C4, with an efficiency about 10% that of active MASP-2. Comparison of the zymogen and active structures of MASP-2 reveals that, in addition to the activation domain, other loops of the serine protease domain undergo significant conformational changes. This additional flexibility could play a key role in the transition of zymogen MASP-2 into a proteolytically active form. Based on the three-dimensional structures of proenzyme and active MASP-2 catalytic fragments, we present model for the active zymogen MASP-2 complex and propose a mechanism for the autoactivation process.

Original languageEnglish
Pages (from-to)33435-33444
Number of pages10
JournalJournal of Biological Chemistry
Issue number39
Publication statusPublished - Sep 30 2005


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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