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GPL Ghostscript 9.14
2019-01-14T14:10:53+01:00
2019-01-14T12:19:20+01:00
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In vitro study of the structure / function relationship of the proteins GASP-1 AND GASP-2 : Involvement of the second Kunitz domain in the functional duality of the GASP proteins
Al Mansi Montasir
Les muscles squelettiques, responsables des mouvements volontaires tels que la locomotion ou le maintien de la posture, représentent environ 40% de la masse corporelle.Cette masse musculaire est maintenue par plusieurs voies de signalisation qui régulent entre autres l’équilibre entre la synthèse et la dégradation des protéines myofibrillaires. En ciblant la voie de signalisation Akt/mTOR, la myostatine est un régulateur négatif de la myogenèse. Elle inhibe la différentiation myogénique et le renouvellement cellulaire. Parmi les différents facteurs moléculaires extracellulaires qui régulent la myostatine, les protéines GASP (Growth and differentiation factor Associated Serum Protein) ont été décrites comme des antagonistes de son activité. L’Unité de Génétique Animale a développé plusieurs stratégies qui permettent d’appréhender les mécanismes moléculaires qui régissent le(s) rôle(s) des protéines GASP au cours du développement musculaire. Ainsi, la création de la lignée murine appelée surGasp-1-20 a permis de montrer que la surexpression de Gasp-1 entraîne un phénotype hypermusclé associé à une hypertrophie des myofibrilles. Une analyse de l’expression génique dans des myoblastes dérivés des cellules satellites montre une surexpression de la myostatine corrélant avec une absence d’hyperplasie chez les souris surGasp-1-20. Des études similaires actuellement en cours pour la protéine GASP-2 devraient permettre de préciser son rôle dans le contexte musculaire. Les protéines GASP sont également définies comme des inhibiteurs composés hétérotypiques caractérisés par plusieurs domaines inhibiteurs pouvant moduler l’activité de différentes protéases. Parmi ces différents domaines,le second domaine Kunitz de GASP-2 a été précédemment décrit comme pouvant inhiber la trypsine. Dans ce travail, nous avons pu montrer que les deux protéines entières conservent cette capacité d’inhibition. Nos résultats indiquent cependant que GASP-1 et GASP-2 présentent une différence de spécificité due à la composition du second domaine Kunitz et non à l’environnement moléculaire présent dans chacune des protéines. Enfin, nous proposons un modèle structural du second domaine Kunitz impliqué dans la dualité fonctionnelle dans l'inhibition anti-trypsine de GASP-1 et GASP-2.
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