A novel mechanoenzymatic cleavage mechanism underlies Transthyretin amyloidogenesis
Mardi 25 juillet 2017 11:00
- Duree : 1 heure
Lieu : CIBB Seminar Room, ILL - 71 avenue des Martyrs - Grenoble
Orateur : Vittorio BELLOTTI & Alessandra CORAZZA (UCL, London)
The mechanisms underlying transthyretin-related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo deposits suggests that a proteolytic cleavage has a crucial pathogenic role. We have shown that the proteolysis/fibrillogenesis pathway is common to several amyloidogenic variants of transthyretin and requires the action of biomechanical forces provided by the shear stress of physiological fluid flow. This may be particularly important in the heart where shear stress is greatest. Discovery of this mechanism of TTR amyloidogenesis offers the opportunity to investigate the potency of TTR ligands under clinical evaluation, or in the pipeline for a pharmaceutical exploitatio.
These ligands can inhibit cleavage-mediated fibrillogenesis with different efficiency and inhibition reaches the highest efficiency when both binding sites and the inner channel are simultaneously occupied. Recent NMR data illuminate on the long distance effect played by TTR ligands and provide a structural explanation for the protection against the proteolytic cleavage.
Contact : mader@ill.fr
Discipline évènement : (Biologie / Chimie)
Entité organisatrice : (ILL)
Nature évènement : (Séminaire)
Site de l'évènement : Polygone scientifique
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