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  Structural basis for the activation of human procaspase-7

Riedl, S. J., Fuentes-Prior, P., Renatus, M., Kairies, N., Krapp, S., Huber, R., et al. (2001). Structural basis for the activation of human procaspase-7. Proceedings of the National Academy of Sciences of the United States of America, 98(26), 14790-14795.

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Genre: Journal Article
Alternative Title : Proc. Natl. Acad. Sci. U. S. A.

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 Creators:
Riedl, S. J., Author
Fuentes-Prior, P.1, Author              
Renatus, M., Author
Kairies, N.1, Author              
Krapp, S.1, Author              
Huber, R.1, Author              
Salvesen, G. S., Author
Bode, W.1, 2, 3, Author              
Affiliations:
1Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              
2Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              
3Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565144              

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 Abstract: Caspases form a family of proteinases required for the initiation and execution phases of apoptosis. Distinct proapoptotic stimuli lead to activation of the initiator caspases-8 and -9, which in turn activate the common executioner caspases-3 and -7 by proteolytic cleavage. Whereas crystal structures of several active caspases have been reported, no three-dimensional structure of an uncleaved caspase zymogen is available so far. We have determined the 2.9-Angstrom crystal structure of recombinant human C285A procaspase-7 and have elucidated the activation mechanism of caspases. The overall fold of the homodimeric procaspase-7 resembles that of the active tetrameric caspase-7. Each monomer is organized in two structured subdomains connected by partially flexible linkers, which asymmetrically occupy and block the central cavity, a typical feature of active caspases. This blockage is incompatible with a functional substrate binding site/active site. After proteolytic cleavage within the flexible linkers, the newly formed chain termini leave the cavity and fold outward to form stable structures. These conformational changes are associated with the formation of an intact active-site cleft. Therefore, this mechanism represents a formerly unknown type of proteinase zymogen activation.

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Language(s): eng - English
 Dates: 2001-12-18
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 35027
ISI: 000172848800013
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Title: Proceedings of the National Academy of Sciences of the United States of America
  Alternative Title : Proc. Natl. Acad. Sci. U. S. A.
Source Genre: Journal
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Publ. Info: -
Pages: - Volume / Issue: 98 (26) Sequence Number: - Start / End Page: 14790 - 14795 Identifier: ISSN: 0027-8424