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Nouveaux variants d'épissage de l'Adenylyl cyclase 8 : de la caractérisation fonctionnelle vers la cible thérapeutique

Abstract : Vascular smooth muscle cells (VSMC) transdifferenciation is a key component in initiation and progression of atherosclerotic lesions and in post-angioplasty restenosis. The work of our team showed that the de novo expression of Adenylyl Cyclase (AC) 8 is involved in VSMCs transdifferenciation. AC8, absent from healthy artery, can be detected in atherosclerotic lesions. However, many studies demonstrate the vasculoprotective effect of cAMP signaling. AC8 proteins form rat transdifferenciated VSMCs in fact represent 4 new splice-variants, the AC8E-H. They are all missing the 5 first transmembrane domains compared to the full-size AC8 (AC8A) and exert a dominant-negative effect by heterodimerizing with functional endogenous ACs. The peptide motifs involved in the heterodimerization of AC8E with other ACs were identified by using a PEPscan approach. This allowed to produce 10 candidate peptides for disrupting AC8E heterodimerization with AC3 and AC6, and thus restore the ability of transdifferenciated VSMCs to produce cAMP. In parallel, modeling the 3D structures of AC3, AC8A and AC8E positions the N-terminal and C1b domains symmetrically around the helical region of these AC. This architecture, with the biochemical data, reveals how these 2 domains regulate the catalytic site conformation, and thus its activity. The AC8E/AC3 complex, currently in modeling, will allow to assess the efficacy of interference of the candidate peptides and to optimize them.
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Submitted on : Friday, July 23, 2021 - 12:28:13 PM
Last modification on : Monday, July 26, 2021 - 2:36:42 PM

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  • HAL Id : tel-03297248, version 1

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Yohan Legueux-Cajgfinger. Nouveaux variants d'épissage de l'Adenylyl cyclase 8 : de la caractérisation fonctionnelle vers la cible thérapeutique. Biologie cellulaire. Sorbonne Université, 2021. Français. ⟨NNT : 2021SORUS005⟩. ⟨tel-03297248⟩

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