Issue |
Med Sci (Paris)
Volume 18, Number 1, Janvier 2002
|
|
---|---|---|
Page(s) | 111 - 120 | |
Section | Forum : Hypothèses Et Débats | |
DOI | https://doi.org/10.1051/medsci/2002181111 | |
Published online | 15 January 2002 |
LEI / L-DNase II : les implications structurales d’un détournement de fonction
LEI / L-DNase II: structural implications of a dual enzymatic activity
Inserm U 450, Développement, vieillissement et pathologie de la rétine, 15, rue de l’École de Médecine, 75006 Paris, France
La LEI (leukoçyte elastase inhibitor) est une protéine appartenant à la superfamille des serpines, qui regroupe des inhibiteurs de protéases d’un type particulier impliqués dans de nombreux processus physiologiques et pathologiques. L’originalité de leur mode d’action réside dans la modification conformationnelle qu’ils subissent après avoir été reconnus comme substrats puis coupés par la protéase qu’ils inhibent, celle-ci étant alors piégée dans un complexe particulièrement stable. Au cours de l’évolution, plusieurs serpines ont mis à profit cette modification conformationnelle pour acquérir une nouvelle fonction, sans rapport avec la première. Ainsi nous avons montré que la LEI acquiert une activité DNase après coupure par l’élastase, activité mise évidence au cours de processus apoptotiques. Nous montrons ici comment l’analyse structurale de la molécule est en accord avec cette deuxième fonction, en révélant des structures compatibles avec un site actif DNase et une translocation nucléaire.
Abstract
LEI (leucocyte elastase inhibitor) is a protein of the Serpin (serine protease inhibitor) superfamily. Most ser-pins display protease inhibiting activity that is involved in many pathological and physiological processes such as coagulation, fibrinolysis, complement activation, angiogenesis, apoptosis, inflammation, neoplasia and viral pathogenesis. Inhibitory serpins are recognized as substrates and cleaved by their specific proteases. The inhibiting process is mediated by the conformationa modification induced in the serpin by this cleavage, which traps the protease in a covalent protease/anti-protease complex. During evolution, many serpins have used this conformational modification to aquire a new activity. For example the cleaved form of antithrombin has been demonstrated to have an antiangiogenic activity. We have previously shown that, in the same way, LEI displays an endonuclease activity after elastase cleavage occuring during apoptosis and we have named this cleaved form “L-DNase II”. Here we show that structura analysis fits to this dual activity (anti-protease /endonuclease), since a putative DNase active site and a nuclear localization signal (NLS) were demonstrated on both its primary and 3D structure. The 3D analysis shows how the conformational modification unmasks this NLS, allowing the L-DNase II to enter the nucleus and degrade DNA. This might therefore explain why both activities are mutually exclusive, making of LEI a putative molecu-ar switch between cell survival and cell death.
© 2002 médecine/sciences - Inserm / SRMS
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