J. Marcoux
A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis
Marcoux, J.; Mangione, P.P.; Porcari, R.; Degiacomi, M.T.; Verona, G.; Taylor, G.W.; Giorgetti, S.; Raimondi, S.; Sanglier-Cianférani, S.; Benesch, J.L.; Cecconi, C.; Naqvi, M.M.; Gillmore, J.D.; Hawkins, P.N.; Stoppini, M.; Robinson, C.V.; Pepys, M.B.; Bellotti, V.
Authors
P.P. Mangione
R. Porcari
Dr Matteo Degiacomi matteo.t.degiacomi@durham.ac.uk
Associate Professor
G. Verona
G.W. Taylor
S. Giorgetti
S. Raimondi
S. Sanglier-Cianférani
J.L. Benesch
C. Cecconi
M.M. Naqvi
J.D. Gillmore
P.N. Hawkins
M. Stoppini
C.V. Robinson
M.B. Pepys
V. Bellotti
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.
Journal Article Type | Article |
---|---|
Acceptance Date | Jul 29, 2015 |
Online Publication Date | Aug 18, 2015 |
Publication Date | Oct 1, 2015 |
Deposit Date | Jul 26, 2017 |
Publicly Available Date | Aug 7, 2017 |
Journal | EMBO Molecular Medicine |
Print ISSN | 1757-4676 |
Electronic ISSN | 1757-4684 |
Publisher | EMBO Press |
Peer Reviewed | Peer Reviewed |
Volume | 7 |
Issue | 10 |
Pages | 1337-1349 |
DOI | https://doi.org/10.15252/emmm.201505357 |
Public URL | https://durham-repository.worktribe.com/output/1380879 |
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Copyright 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.
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