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The conformational modification of serpins transforms Leukocyte Elastase Inhibitor into an endonuclease involved in apoptosis.

Abstract : The best characterized biochemical feature of apoptosis is degradation of genomic DNA into oligonucleosomes. The endonuclease responsible for DNA degradation in caspase-dependent apoptosis is Caspase Activated DNase (CAD). In caspase-independent apoptosis, different endonucleases may be activated according to the cell line and the original insult. Among the known effectors of caspase-independent cell death, L-DNase II (LEI derived DNase II) has been previously characterized by our laboratory. We have thus shown that this endonuclease derives from a serpin super-family member LEI (Leukocyte Elastase Inhibitor) by post-translational modification [Torriglia et al, (1998) Mol. Cell. Biol 18, 3612-3619]. In this work we assessed the molecular mechanism involved in the change of the enzymatic activity of this molecule from an anti-protease to an endonuclease. We report that the cleavage of LEI by elastase at its reactive center loop abolishes its anti-protease activity and leads to a conformational modification that exposes an endonuclease active site and a Nuclear Localization Signal (NLS). This represents a novel molecular mechanism for a complete functional conversion induced by the conformational change of a serpin. We also show that this molecular transformation affects cellular fate and that both endonuclease activity and nuclear translocation of L-DNase II, are needed to induce cell death.
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https://www.hal.inserm.fr/inserm-00140748
Contributor : Alicia Torriglia <>
Submitted on : Tuesday, April 10, 2007 - 1:49:41 PM
Last modification on : Monday, August 26, 2019 - 12:02:03 PM
Long-term archiving on: : Tuesday, April 6, 2010 - 11:07:48 PM

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Laura Padron-Barthe, Chloé Leprêtre, Elisabeth Martin, Marie-France Counis, Alicia Torriglia. The conformational modification of serpins transforms Leukocyte Elastase Inhibitor into an endonuclease involved in apoptosis.. Molecular and Cellular Biology, American Society for Microbiology, 2007, pp.10.1128. ⟨10.1128/MCB.01959-06⟩. ⟨inserm-00140748⟩

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