Crystal structure of a procaspase-7 zymogen: Mechanisms of activation and substrate binding

Citation
Jj. Chai et al., Crystal structure of a procaspase-7 zymogen: Mechanisms of activation and substrate binding, CELL, 107(3), 2001, pp. 399-407
Citations number
39
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell & Developmental Biology
Journal title
CELL
ISSN journal
0092-8674 → ACNP
Volume
107
Issue
3
Year of publication
2001
Pages
399 - 407
Database
ISI
SICI code
0092-8674(20011102)107:3<399:CSOAPZ>2.0.ZU;2-K
Abstract
Apoptosis is primarily executed by active caspases, which are derived from the inactive procaspase zymogens through proteolytic cleavage. Here we repo rt the crystal structures of a caspase zymogen, procaspase-7, and an active caspase-7 without any bound inhibitors. Compared to the inhibitor-bound ca spase-7, procaspase-7 zymogen exhibits significant structural differences s urrounding the catalytic cleft, which precludes the formation of a producti ve conformation. Proteolytic cleavage between the large and small subunits allows rearrangement of essential loops in the active site, priming active caspase-7 for inhibitor/substrate binding. Strikingly, binding by inhibitor s causes a 180 degrees flipping of the N terminus in the small subunit, whi ch interacts with and stabilizes the catalytic cleft. These analyses reveal the structural mechanisms of caspase activation and demonstrate that the i nhibitor/substrate binding is a process of induced fit.