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A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis.

Marcoux, J. and Mangione, P.P. and Porcari, R. and Degiacomi, M.T. and Verona, G. and Taylor, G.W. and Giorgetti, S. and Raimondi, S. and Sanglier-Cianférani, S. and Benesch, J.L. and Cecconi, C. and Naqvi, M.M. and Gillmore, J.D. and Hawkins, P.N. and Stoppini, M. and Robinson, C.V. and Pepys, M.B. and Bellotti, V. (2015) 'A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis.', EMBO molecular medicine., 7 (10). pp. 1337-1349.

Abstract

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 role in destabilizing the tetramer and releasing the highly amyloidogenic 49–127 truncated protomer. Here, we investigate the mechanism of cleavage and release of the 49–127 fragment from the prototypic S52P variant, and we show 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. Crucially, the non‐amyloidogenic and protective T119M variant is neither cleaved nor generates fibrils under these conditions. We propose that a mechano‐enzymatic mechanism mediates transthyretin amyloid fibrillogenesis in vivo. This may be particularly important in the heart where shear stress is greatest; indeed, the 49–127 transthyretin fragment is particularly abundant in cardiac amyloid. Finally, we show that existing transthyretin stabilizers, including tafamidis, inhibit proteolysis‐mediated transthyretin fibrillogenesis with different efficiency in different variants; however, inhibition is complete only when both binding sites are occupied.

Item Type:Article
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Status:Peer-reviewed
Publisher Web site:https://doi.org/10.15252/emmm.201505357
Publisher statement:© 2015 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Date accepted:29 July 2015
Date deposited:07 August 2017
Date of first online publication:18 August 2015
Date first made open access:No date available

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