期刊
EMBO MOLECULAR MEDICINE
卷 7, 期 10, 页码 1337-1349出版社
WILEY
DOI: 10.15252/emmm.201505357
关键词
amyloid; mechano-enzymatic cleavage; transthyretin
资金
- UK Medical Research Council [MR/K000187/1]
- Italian Ministry of University and Research (MIUR) [FIRB RBFR109EOS]
- Cariplo Foundation [2014-0700]
- MIUR [17DPXLNBEK]
- MIUR Basic Research Investment Fund [FIRB RBPR05JH2P]
- Swiss National Science Foundation [P2ELP3_155339]
- Istituto Nazionale di Biostrutture e Biosistemi
- UCL Amyloidosis Research Fund
- UK National Institute for Health Research Biomedical Research Centre and Unit Funding Scheme
- Biotechnology and Biological Sciences Research Council [BB/K004247/1] Funding Source: researchfish
- Medical Research Council [MR/K000187/1, G7900510] Funding Source: researchfish
- Rosetrees Trust [M427] Funding Source: researchfish
- Swiss National Science Foundation (SNF) [P2ELP3_155339] Funding Source: Swiss National Science Foundation (SNF)
- BBSRC [BB/K004247/1] Funding Source: UKRI
- MRC [MR/K000187/1, G7900510] Funding Source: UKRI
The mechanisms underlying transthyretin-related amyloidosis invivo remain unclear. The abundance of the 49-127 transthyretin fragment in exvivo 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 invivo. 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.
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