A true autoactivating enzyme

Structural insight into mannose-binding lectin-associated serine protease-2 activations

P. Gál, V. Harmat, Andrea Kocsis, Tünde Bián, László Barna, Géza Ambrus, Barbara Végh, Júlia Balczer, Robert B. Sim, G. Náray-Szabó, P. Závodszky

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

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
Volume280
Issue number39
DOIs
Publication statusPublished - Sep 30 2005

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Mannose-Binding Lectin
Serine Proteases
Enzyme Precursors
Chemical activation
Enzymes
Complement Activation
Lectins
Crystal structure

ASJC Scopus subject areas

  • Biochemistry

Cite this

A true autoactivating enzyme : Structural insight into mannose-binding lectin-associated serine protease-2 activations. / Gál, P.; Harmat, V.; Kocsis, Andrea; Bián, Tünde; Barna, László; Ambrus, Géza; Végh, Barbara; Balczer, Júlia; Sim, Robert B.; Náray-Szabó, G.; Závodszky, P.

In: Journal of Biological Chemistry, Vol. 280, No. 39, 30.09.2005, p. 33435-33444.

Research output: Contribution to journalArticle

Gál, P. ; Harmat, V. ; Kocsis, Andrea ; Bián, Tünde ; Barna, László ; Ambrus, Géza ; Végh, Barbara ; Balczer, Júlia ; Sim, Robert B. ; Náray-Szabó, G. ; Závodszky, P. / A true autoactivating enzyme : Structural insight into mannose-binding lectin-associated serine protease-2 activations. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 39. pp. 33435-33444.
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